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132 results on '"Karolinska Inst"'

1. Reading and Writing Difficulties--A Problem? EMIR Education and Research.

Author: Eve Malmquist Inst. for Reading, Savsjo (Sweden)., Karolinska Inst., Stockholm (Sweden)., Ericson, Britta, Ericson, Britta, Eve Malmquist Inst. for Reading, Savsjo (Sweden)., and Karolinska Inst., Stockholm (Sweden).
Abstract: This collection of essays contains a brief description of the symptoms of dyslexia and a definition of the terminology. The meaning of being the mother of a dyslexic child and how to live with this "hidden handicap" are also described. Suggestions regarding how to treat persons with reading and writing difficulties are put forward. After a foreword and an introduction, the essays are: "Reading and Writing Difficulties and Dyslexia (Britta Ericson); "Living with a Handicap" (Birgitta Johansson); "To Be Seen as a Person" (Kajsa Stening); "Walking with Your Child Side by Side" (Katarina Stening); "How To Deal with People Having Reading and Writing Difficulties" (Birgitta Johansson and Kajsa Stening; "A Few Thoughts on Dyslexia" (Serge Garcet); and "Reading and Writing Difficulties form a Belgian Point of View" (Arlette Paulissen). (Author/RS)
Published: 1999

2. Tackling adversity through innovation: A pilot study exploring VR as a tool to identify and diagnose depression

Author: S. Sutori and Karolinska Institutet: E. Eliasson, G. Hadlaczky, I. Todorov, V. Carli; University of Padua: F. Mura, V. Cardi; Polytechnic University of Valencia: V. Ortiz, M.A. Raya; University of Pisa: A.L. Alfeo, V. Catrambone, G. Valenza
Subjects: Psychiatry, RC435-571
Abstract: Abstract Introduction The final aim of the EXPERIENCE project is to enable individuals to record and share extended-personal realities in Virtual Reality (VR) - which entails the consideration of a person’s neurophysiological, psychological, and cognitive states. One prospective application is using this technology to aid in assessing symptoms of affective disorders. Objectives The objective is to test the ability of a pre-designed VR environment to differentiate between individuals with depressive symptoms and healthy controls (HCs) via machine learning algorithms. Methods Conducted as a pilot study in Italy, we recruited 100 volunteers, comprising 50 HCs and 50 individuals with moderate depressive symptoms assessed via the PHQ-9. Through a 40–60-minute VR engagement, comprehensive data on cognitive (inc. cognitive flexibility, sustained attention, working memory, processing speed), behavioral (exploration, attentional bias), and physiological (heart-rate variability, skin conductance) variables was collected. Subsequently, an explainable artificial intelligence model (xAI) was trained on data from 80% of the sample and tested on the remaining 20% in terms of accuracy for between-group classification. Results Following an iterative process that considered both the importance assigned to each variable in the different models and the theoretical relevance of these variables to depression the final model achieved an average accuracy of 71% (with individual trials ranging from 64.5% to 77.1%). Key predictors included exploratory behaviors and heart-rate variability during both exploration and cognitive tasks. Conclusions These results are comparable, however remain below the levels of accuracy achieved based on fMRI and DTI data alone (around 80%). Nonetheless, the EXPERIENCE system, slated for refinement beyond this pilot phase, shows potential in integrating multimodal data for evaluating affective disorder symptoms, aiming for a more objective screening and diagnostic approach at a lower cost. Acknowledgement The EXPERIENCE project is funded by the European Commission H2020 Framework Program, Grant No. 101017727. Disclosure of Interest None Declared
Published: 2024
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3. Evaluation of Factors Determining the Results of Vocational Rehabilitation. Norwegian Monographs on Medical Science.

Author: Karolinska Inst., Stockholm (Sweden)., Norwegian State Rehabilitation Inst., Bergen., Bergen Univ. (Norway)., and Gogstad, Anders C.
Abstract: Physical disability from disease or injury often results in a permanent state of social insufficiency, especially when the disability is reinforced by individual or environmental factors. In a study of almost 700 persons treated at a Norwegian rehabilitation center, regression analysis was used to compare those who benefited from the program with those who did not. The hypothesis tested was basically that the population referred to the institute differed significantly from the region's general population in several respects. The investigation found complex relationships between variables, with the most significant failure characteristics being age and mental disturbance. The study stressed the need to counteract passive dependence, in order to strengthen self-confidence and motivation. (BH)
Published: 1968

4. Metabolomics and Prostate Cancer

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Wiklund, Fredrik, KAROLINSKA INST STOCKHOLM (SWEDEN), and Wiklund, Fredrik
Abstract: We performed untargeted serum metabolomic profiling of two large population-based prostate cancer populations. Molecular features have been derived and explored for association with prostate cancer status (6,138 features, 475 subjects) and prostate cancer survival (5,209 features, 534 subjects). Assessment of metabolite features revealed two features as studywide significantly associated with prostate cancer status; however, due to low observed abundance we were not able to identify the molecular identity of these features. Among features indicated in pairwise analysis molecular identification revealed Caprolactam, L-Phosphatidic acid, and Peptide (Tyr-Lys-Thr) as possibly associated with prostate cancer aetiology. Genomewide assessment of the four top associated metabolite features implicated four genes PDE7B, NRG3, ILI3RA1 and UGT3A1 of which the association between metabolite feature 174.1_53 and gene ILI3RA1 was genome-wide significant (P = 1.4 x 10-8). This finding is interesting since although IL13RA1 itself has not been associated with prostate cancer, the alpha 2 chain of the same receptor (IL13RA2) has been reported to be differentially expressed in a metastatic prostate cancer cell line, and suggested as a target for prostate cancer treatment. In summary, several metabolite features associated with prostate cancer were discovered that warrant further investigation to advance our understanding of the underlying biological processes., The original document contains color images.
Published: 2013

5. Which Implant Is Best After Failed Treatment for Pathologic Femur Fractures?

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Forsberg, Jonathan A, Wedin, Rikard, Bauer, Henrik, KAROLINSKA INST STOCKHOLM (SWEDEN), Forsberg, Jonathan A, Wedin, Rikard, and Bauer, Henrik
Abstract: Successful treatment of pathologic femur fractures can preserve a patient's independence and quality of life. The choice of implant depends on several disease and patient-specific variables; however, its durability must generally match the patient's estimated life expectancy. Failures do occur, however, it is unclear which implants are associated with greater risk of failure. We evaluated patients with femoral metastases in whom implants failed to determine (1) the rate of reoperation; (2) the timing of and most common causes for failure; and (3) incidence of perioperative complications and death., SYMPOSIUM: PAPERS PRESENTED AT THE 2011 ISOLS MEETING IN BEIJING, CHINA, Sept 15-18, 2011, Published in Clinical Orthopaedics and Related Research, Sept. 5, 2012, Government or Federal Purpose Rights License. The original document contains color images.
Published: 2012

6. A Novel Approach to Detect Therapeutic Resistance in Breast Cancer

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Czene, Kamila, KAROLINSKA INST STOCKHOLM (SWEDEN), and Czene, Kamila
Abstract: Our aim is to understand whether adjuvant therapy of a first primary breast cancer might predict the prognosis of a metachronous bilateral cancer. Major findings: Our findings support a selection process where adjuvant systemic treatment selectively prevents the occurrence of cancers with a favourable prognosis, allowing those with a more aggressive phenotype to surface clinically., The original document contains color images.
Published: 2008

7. A Novel Approach to Detect Therapeutic Resistance in Breast Cancer

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Czene, Kamila, KAROLINSKA INST STOCKHOLM (SWEDEN), and Czene, Kamila
Abstract: Purpose/scope: Our aim is to understand whether adjuvant therapy of a first primary breast cancer might predict the prognosis of a metachronous bilateral cancer. Major findings: Our findings support a selection process where adjuvant systemic treatment selectively prevents the occurrence of cancers with a favourable prognosis, allowing those with a more aggressive phenotype to surface clinically. Up-to- date report: We have requested for a no-cost extension of the project due to difficulties with collection of tissue samples., The original document contains color images.
Published: 2007

8. A Population-Based Study of Dietary Acrylamide and Prostate Cancer Risk

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Adami, Hans-Olov, KAROLINSKA INST STOCKHOLM (SWEDEN), and Adami, Hans-Olov
Abstract: The aim of this study is to determine whether intake of foods found to have high levels of acrylamide increase the risk of prostate cancer among men. Methods: A population-based case-control study on prostate cancer. The exposure to acrylamide was estimated by using a food frequency questionnaire (FFQ) and by hemoglobin adducts in blood. Results: The intake of acrylamide and adduct levels are in line with previous studies, but there was only a weak correlation between the two estimates. The relative risk of prostate cancer was 0.97 (95% CI 0.75-1.27) for the highest quintile of exposure compare to the lowest quintile. Conclusions: ""There was no evidence of an overall association between exposure to dietary acrylamide and prostate cancer risk in the present study., The original document contains color images.
Published: 2007

9. A Population-Based Study of Dietary Acrylamide and Prostate Cancer Risk

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Adami, Hans-Olov, KAROLINSKA INST STOCKHOLM (SWEDEN), and Adami, Hans-Olov
Abstract: The aim of this study is to determine whether intake of foods found to have high levels of acrylamide increase the risk of prostate cancer among men. Major findings: We have finished the data collection in a population-based case-control study on prostate cancer. The daily median intake of acrylamide was 43 microgram in the control group. Up-to-date report: The project is up and running but due to problems with the laboratory method for analysis of DNA adducts of acrylamide and the delayed payment from US army we have been granted one additional year in order to finish the tasks for months 13-29 (see "Research accomplishments"). We foresee no problems in completing them on schedule.
Published: 2006

10. Breast Cancer - A Disease of a Susceptible Subgroup of Women

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Hall, Per, KAROLINSKA INST STOCKHOLM (SWEDEN), and Hall, Per
Abstract: Background: The risk of bilateral breast cancer is substantially higher than the risk of unilateral disease and associated with early age at onset of the initial breast cancer. Of the many established risk factors for breast cancer, only family history has been consistently shown to be associated with bilateral disease. Methods: We analyzed a population-based cohort of 123,757 women with a first primary breast cancer diagnosed in Sweden from 1970 to 2000 and identified 6,550 women with a bilateral breast cancer. Results: Incidence of synchronous bilateral breast cancer mimics that of unilateral breast cancer. During 20 years from initial diagnosis, the incidence of metachronous cancer decreased from about 800 to 400 per 10(exp 5) person-years in patients first diagnosed before age 45, whilst the incidence remained stable at 500 to 600 per 10(exp 5) among those who were older at diagnosis of first cancer. Conclusions: The finding of breast cancer being simultaneously diagnosed in two breasts has an incidence far beyond the expected, but is probably not explained by genetic background rather environmental factors. The incidence pattern of metachronous bilateral cancer by age and follow-up time fits neither a model of highly penetrant genes, nor a model assuming only aggregation of environmental risk factors.
Published: 2004

11. A 3D-Model for Computer Simulation of Atrial Electrophysiology

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Fredby, Magnus, Elmqvist, Hakan, KAROLINSKA INST STOCKHOLM (SWEDEN), Fredby, Magnus, and Elmqvist, Hakan
Abstract: The presented implementation is a three-dimensional isotropic monodomain reaction-diffusion model with a realistic geometry coupled with the atrial ion model proposed by Nygren et al. The partial differential equations are solved by a Garlekin finite element method in space and a forward Euler approximation in time. Simulations yields the expected results and the computational performance of the model is good considering the size of the problem., Papers from the 23rd Annual International Conference of the IEEE ENgineering in Medicine and Biology Society, October 25-28, 2001, held in Istanbul, Turkey. See also ADM001351 for entire conference on cd-rom., The original document contains color images.
Published: 2001

12. Extreme Prematurity and the Risk of Breast Cancer - A Cohort Study

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Ekbom, Anders, KAROLINSKA INST STOCKHOLM (SWEDEN), and Ekbom, Anders
Abstract: Purpose: To analyze to what extent women born extreme premature and women characterized as small for gestational age at birth differ with regards to breast cancer risk as adults. Scope: To identify all women within a study base of 290,000 female births during the years 1925 to 1949 in central Sweden born before the 35th gestational week and/or with a birth weight below 2,000 grams. The women in the cohort still alive in 1958 have been followed up for occurrence of breast cancer through linkage with Swedish registries. Major findings: There were 1,847 survivors January 1, 1958, of which 90 were diagnosed with breast cancer up through 1996. Preliminary analyses strongly indicate that women born extremely premature compared to those born small for gestational age have an increased risk of breast cancer. Conclusion: Our findings strongly indicate that early hormonal exposures are of importance for the risk of breast cancer later in life.
Published: 2000

13. High-Throughput Array Instrument for DNA-Based Breast Cancer Diagnostics

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Swerdlow, Harold P., KAROLINSKA INST STOCKHOLM (SWEDEN), and Swerdlow, Harold P.
Abstract: The aim of this project is to develop improved methods for the production, processing, and analysis of microarrays (gene-chips) for breast-cancer diagnostics. These methods are based upon large numbers of discrete DNA spots placed on glass microscope slides typically, and hybridized to a probe derived from a tIssue or blood sample. %or breast- cancer diagnostics, there are two likely predominant modes of use. TIssue samples from suspect lesions, e.g., can be assessed for patterns of gene expression on cDNA arrays, indicative of a specific disease type or state. Additionally, analysis of known mutations can be performed on oligonucleotide-based arrays. We are optimizing cDNA microarray methods, and have achieved excellent limits of detection, although not good enough to detect the rarest transcripts. To improve this situation, we are redesigning our novel imaging (non-scanning) fluorescence microarray reader that currently performs four times better (with respect to limit of detection) than a commercial scanner, and does so about 300 times faster. Our next goal is to implement oligonucleotide arrays by various methods including both padlock probe-based ligation assays and allele-specific hybridization tests for specific known mutations. We are also actively improving direct covalent attachment of oligonucleotides to glass, and methods for printing oligonucleotide arrays much faster and cheaper.
Published: 2000

14. Individual Differences in Reactions to Irregular Work Hours

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Akerstedt, Torbjorn, KAROLINSKA INST STOCKHOLM (SWEDEN), and Akerstedt, Torbjorn
Abstract: This limited review suggests that some traditional factors like, personality and circadian amplitude seem to have little to do with tolerance of shift work. Neither does gender, at least not if social responsibility is controlled for. Age on the other hand seems of more interest and also diurnal type, but the two seem closely related. However, the major determinants of shift work tolerance probably have more to do with states or rather ways of coping with irregular work hours. Thus, the way an individual organizes his behavior to promote sleep may be of importance, as may be the need for sleep. This may be related to commitment to night work, avoiding light after night work, etc. One should probably give priority to teaching sleep/wake optimization, rather than trying to find individuals with particular traits. One gets the feeling that the highly tolerant single night shift worker would be older, have a low need for sleep, have a high sleep quality, be in good physical shape, and plan sleep strategically (using naps). If several night shifts occur in sequence, younger individuals may have an advantage., Presented at the RTO Human Factors and Medicine Panel, Venice, Italy, 3-4 June 99. This article is from ADA388183 Individual Differences in the Adaptability to Irregular Rest-Work Rhythms/Status of the Use of Drugs in Sleep-Wakefulness Management (les Differences entre individus concernant les facultes d'adaptation aux rythmes irreguliers activite-repos/Le point sur 1'utilisation des medicaments pour la gestion des periodes veille-sommeil)
Published: 2000

15. A Capillary Instrument for High Speed DNA-Based Tumor Diagnosis

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Swerdlow, Harold P., KAROLINSKA INST STOCKHOLM (SWEDEN), and Swerdlow, Harold P.
Abstract: This project addresses the design and prototyping of a multiple-capillary (ultimately 96- channel) electrophoresis system that will be ideally suited for the rapid and inexpensive analysis of allele-specific and DNA-sequence-based breast-cancer diagnostic tests with high throughput. A fully- automated capillary electrophoresis system (as opposed to an electrophoresis instrument) will perform the following steps without human intervention: 1) prepare and purify DNA, ideally from blood or tissue samples, 2) mix DNA samples with PCR reagents, 3) thermally cycle and purify PCR products, 4) mix PCR samples with DNA sequencing reagents, 5) perform sequencing reactions (thermal cycling typically) and purify the fragments, 6) pre-run the capillaries and load the samples, 7) perform the electrophoresis and detect the DNA bands, 8) record and analyze the data, and 9) flush the capillaries after the previous run and fill the capillaries with fresh polymer solution. The present study will automate steps 6-9 of this process.
Published: 1999

16. Extreme Prematurity and the Risk of Breast Cancer - A Cohort Study.

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Ekbom, Anders R., KAROLINSKA INST STOCKHOLM (SWEDEN), and Ekbom, Anders R.
Abstract: All the necessary approvals from the different government agencies such as the Swedish Data Inspection Board, the Swedish Cancer Registry, the Swedish Death Registry and the Swedish Emigration Registry have been procured. Two abstractors have been employed and are presently working in the different archives. They are presently retrieving information from the ledgers and also tracing the women through the population ledgers. Until now, May 1, just over 100,000 female births have been assessed yielding the expected number of those born extreme premature and/or with a birth weight less than 2,000 grams. Thus, the retrieval process is within the framework of the time plan in our proposal and the tracing will be completed in April, 2000.
Published: 1999

17. Human Immunodeficiency Virus (HIV) Infections; Strain and Type Variations; Diagnosis and Prevention.

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Norrby, Erling, Fenyo, Eva M., KAROLINSKA INST STOCKHOLM (SWEDEN), Norrby, Erling, and Fenyo, Eva M.
Abstract: The studies described herein have focused on HIV variability, in particular on biologic and antigenic variability and its relevance for pathogenesis and for development of means for immune intervention. During the third year of the grant period we have intensified studies on molecular variability of HIV-1 and attempted to molecularly map biologic and antigenic determinants. Biologic characterization involved tests for replicative capacity, cytopathic effect and monocyte tropism of virus isolates and molecular clones, whereas antigenic characterization involved virus neutralization in autologous as well as heterologous system. By use of synthetic peptides, epitopes for virus neutralization and antibody dependent cellular cytotoxicity (ADCC) have been mapped in the envelope of HIV-1 and HIV-2. Variable region 3 (V3) of the HIV-1 envelope has been studied in relation to biological and antigenic variation of HIV-1 isolates and in relation to mother-to-child transmission of HIV-1.
Published: 1992

18. Human Immunodeficiency Virus (HIV) Infections: Strain and Type Variations; Diagnosis and Prevention

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Erling, Norrby, Fenyo, Eva M., KAROLINSKA INST STOCKHOLM (SWEDEN), Erling, Norrby, and Fenyo, Eva M.
Abstract: The results show that: (a) the replicative capacity of HIV-2, like HIV-1, correlates with the severity of immunodeficiency; (b) molecular clones of a rapid/high HIV-1 isolate may have restricted replicative capacity compared to the genetically heterogenous isolate. Transfection of the same molecular clones into different cell types may yield progeny viruses with different phenotypes; (c) monocyte tropism is a general property of HIV isolates. In some cases silent infection is established. Silently infected monocyte/macrophages harbor virus that can be recovered by cocultivation with peripheral blood mononuclear cells.
Published: 1991

19. Stereospecificity of Antidotes and Their Mechanism of Action in Intoxications with Organophosphorus Anticholinesterases.

Author: KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF TOXICOLOGY, Holmstedt, Bo., Karlen, Bo, Nordgren, Ingrid, Palmer, Lena, KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF TOXICOLOGY, Holmstedt, Bo., Karlen, Bo, Nordgren, Ingrid, and Palmer, Lena
Abstract: Our program during the grant period has mainly been concerned with studies on: (1) Effect of antidotes such as l-hyoscyamine and atropine, diazepam, and Hl-6, separately and in combinations, on the dynamics of acetylcholine. We found that diazepam counteracts the increased rate of synthesis and release of acetylcholine induced by l-hyoscyamine. The addition of diazepam to conventional atropine-oxime therapy is therefore more effective in cases of organophosphate intoxications. Soman-intoxicated mice pretreated with the three-drug combination show no cholinergic symptoms and have a normal turnover of acetylcholine. (2) Influence of cholinergic substances on the functional muscarinic-receptor pool. Diazepam was found to decrease the size of the active receptor pool, which may lead to the observed effect on the dynamics of acetylcholine and choline.
Published: 1991

20. Stereospecificity of Antidotes and Their Mechanism of Action in Intoxications with Organophosphorus Anticholinesterases

Author: KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF TOXICOLOGY, Holmstedt, Bo, Karlen, Bo, Nordgren, Ingrid, Palmer, Lena, KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF TOXICOLOGY, Holmstedt, Bo, Karlen, Bo, Nordgren, Ingrid, and Palmer, Lena
Abstract: Our program during the last year has mainly been concerned with studies on: the effect of diazepam on 1-hyoscyamine binding in the old stock of sick and healthy mice and new stock of healthy mice, the usability of 1- hyoscyamine binding for studies of specific receptor distribution in brain, effect of different combinations of antagonists (1-hyoscyamine, diazepam, H1-6) on acetycholine turnover, and duration of the effect of diazepam on acetylcholine turnover. There is a significant difference between the old and new stock of mice as far as the influence of diazepam on 1-hyoscyamine binding is concerned. In order that optimal parameters can be determined, therefore, the model needs further development in the new stock of mice. Keywords: Acetylcholine, Choline, Diazepam, Hyoscyamine, HI-6, Cholinesterase inhibitors, RA 5.
Published: 1990

21. Assessment of the endocrine disrupting properties of Bisphenol AF according to the EU criteria and ECHA/EFSA guidance

Author: Karolinska Institutet, Institute of Environmental Medicine, Sweden, Laura Escrivá, Annika Hanberg, Johanna Zilliacus, and Anna Beronius
Subjects: bisphenol AF, endocrine disruptor, risk assessment, Nutrition. Foods and food supply, TX341-641, Chemical technology, TP1-1185
Abstract: Abstract Endocrine disruptors (EDs) are exogenous compounds that interfere with the hormone system, affecting human health and environment. Specific legislative obligations have been introduced in the European Union (EU) to gradually eliminate EDs in water, industrial chemicals and pesticides. However, identification of EDs is the first and essential step towards regulation and appropriate risk management. Scientific criteria and guidance for ED assessment have recently been established for pesticides in the EU. In this project, the ED properties of the non‐pesticide chemical Bisphenol AF (BPAF), analogue and potential substitute of Bisphenol A were evaluated by the application of the EU criteria and guidance in the frame of human health risk assessment. A data dossier was built by a systematic literature review (WOS, Scopus, Pubmed, Embase), title/abstract screening (RAYYAN) and full‐text examination. All relevant information was extracted and systematically reported, and reliability and relevance of data were assessed (SciRAP). Data were synthesised into lines of evidence for (i) endocrine activity, (ii) adversity and (iii) general toxicity, and weight of evidence evaluation was applied. The initial analysis of the evidence showed potential endocrine adverse effects and endocrine activity, meeting the ED criteria and leading the assessment to the mode of action (MoA) analysis. The biological plausibility of the link between the adverse effects and the endocrine activity was investigated based on current scientific knowledge. Empirical support for dose–response and temporal concordance was evaluated, and the key events were assessed in terms of essentiality, consistency, analogy and specificity. Finally, an overall conclusion of the ED properties of BPAF was drawn. The EU criteria and guidance for EDs assessment were successfully applied to BPAF demonstrating its endocrine activity and adversity based on weight of evidence methodology and MoA analysis. The Fellow greatly increased her knowledge and hands‐on experience on ED assessment in the EU regulatory context contributing to implement transparency and structure in health risk assessment.
Published: 2019
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22. Stereospecificity of Antidotes and Their Mechanism of Action in Intoxications with Organophosphorus Anticholinesterases

Author: KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF TOXICOLOGY, Holmstedt, Bo., Karlen, Bo., Nordgren, Ingrid., Palmer, Lena., KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF TOXICOLOGY, Holmstedt, Bo., Karlen, Bo., Nordgren, Ingrid., and Palmer, Lena.
Abstract: In intoxications by organophosphates conventional prophylaxis and therapy by atropine and oximes have shown to benefit from the addition of diazepam treatment. The implication of the cholinergic system in such intoxications prompted us to study the direct effects of diazepam on this system. In this context acetylcholine (ACh) turnover in mouse brain in vivo is a suitable cholinergic model. Turnover of ACh was studied by following the incorporation of Ch into ACh after i.v. injection of deuterated Ch. To study the functional muscarinic receptor pool, we have developed a method utilizing the pharmacologically 'active' antipode of atropine, l-hyoscyamine. By injecting this compound and measuring its concentration in the brain of mice, it is possible to study specific receptor binding. The concentration of l-hyoscyamine after equilibration is assumed to correspond to the size of the functional muscarinic receptor pool. At this concentration, l-hyoscyamine prevented oxotremorine (OT)-induced tremor, confirming its physiological relevance. The effects of diazepam on the ACh dynamics are consistent with diazepam's known potentiation of gamma-aminobutyric acid's inhibitory function in nerve transmission, with a decreased turnover rate of ACh and increased levels of ACh and Ch as results. The modulating effect of diazepam on the binding properties of muscarinic receptors is probably one of the mechanisms responsible for its profound effects in treatment of intoxications with anticholinesterases. Keywords: Antidotes, Cholinesterase inhibitors.
Published: 1988

23. Potential Benefits and Hazards of Humoral Immune Reactions against HTLV-III.

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Wigzell, Hans, KAROLINSKA INST STOCKHOLM (SWEDEN), and Wigzell, Hans
Abstract: Monoclonal murine IgG antibodies against Gp120 from HIV-1 were found to induce significant enhancement of HIV-1 replication in vitro when used at low antibody concentrations. This enhancement was dependent on the presence of FcR:s for IgG and was completely blocked by anti-CD4 monoclonal antibodies. HIV-1 seropositive individuals at a low frequency do produce antibodies reactive with Gp12O and 'mimicking' CD4 molecules as evidenced by their reactivity with certain CD4 monoclonal antibodies. It was, however, not possible to show that such 'mimicking' antibodies were especially efficient in neutralizing, nor was presence of such antibodies linked to a particular clinical progression behaviour. Presence of antibodies to peptides covering the respective cysteins in the V3 loop of a particular HIV-1 isolate were found using two Italian cohorts to be positively linked to a reduced rate of transmission of virus from mother to child.
Published: 1989

24. Potential Benefits and Hazards of Humoral Immune Reactions against HTLV-III.

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), Wigzell, Hans, Gidlund, Magnus, Nilsson, Kenneth, KAROLINSKA INST STOCKHOLM (SWEDEN), Wigzell, Hans, Gidlund, Magnus, and Nilsson, Kenneth
Abstract: Gp120 binding to CD4 requires beta-glycanase sensitive carbohydrate chains to retain binding ability. A 28Kd fragment of Gp120 has been identified with complete retention of CD4 binding capacity. Human monocytes can be readily infected with HIV. In the absence of anti-HIV antibodies, phagocytic or non-phagocytic monocytes are equally sensitive. Anti-HIV antibodies at certain high dilutions may enhance HIV proliferation in human monocytes although exact conditions causing such enhancement are not yet defined. Certain human HIV-seropositive individuals produce high titered antibodies which display molecular mimicry with CD4 and bind to Gp120. Such antibodies may tentatively be linked to good prognosis. Keywords: Human immunodeficiency virus, Immunosuppression, Immunity.
Published: 1987

25. Final Technical Report, November 1961-November 1962

Author: KAROLINSKA INST STOCKHOLM (SWEDEN), HEDEN, C. G., KAROLINSKA INST STOCKHOLM (SWEDEN), and HEDEN, C. G.
Published: 1962

26. CORRELATION OF ION EXCHANGE COLUMN WITH MOLECULAR STRUCTURE OF BONE

Author: KAROLINSKA INST FOR AEROMEDICAL AND NAVAL MEDICAL RESEARCH STOCKHOLM (SWEDEN), CARLSTROM,DIEGO, KAROLINSKA INST FOR AEROMEDICAL AND NAVAL MEDICAL RESEARCH STOCKHOLM (SWEDEN), and CARLSTROM,DIEGO
Published: 1961

27. SUMMARY OF RECENT ADVANCES IN X-RAY MICROCHEMICAL TECHNIQUES.

Author: KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF MEDICAL PHYSICS, Engstrom, Arne, KAROLINSKA INST STOCKHOLM (SWEDEN) DEPT OF MEDICAL PHYSICS, and Engstrom, Arne
Abstract: The development of X-ray analytical methods applicable to the study of problems in cell physiology has advanced considerably in recent years. One can distinguish between methods based on absorption, on diffraction and on emission of X-rays, and these three groups of techniques can now be applied to specimens in the micron range in size. In the present paper the most recent advances in X-ray micro-methods for cell chemical analysis will be briefly summarized. (Author), Sponsored in part by grants from Swedish Medical Research Council and Rockefeller Foundation.
Published: 1961

28. Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia

Author: Stephens, N A, Gallagher, I J, Rooyackers, O, Skipworth, R J, Tan, B H l, Marstrand, T, Ross, J A, Guttridge, D C, Lundell, L, Fearon, K C H, Timmons, J A, Copenhagen, Edinburgh, Heriot-Watt, Karolinska Inst, Sweden, and Ohio State University

29. Implementation of lung cancer CT screening in the Nordic countries

Author: [ 1 ] Univ Copenhagen, Dept Cardiothorac Surg, RT Rigshosp, Copenhagen, Denmark Show more [ 2 ] Rigshosp Copenhagen, Dept Oncol, Finsen Ctr, Copenhagen, Denmark Show more [ 3 ] Gentofte Univ Hosp, Dept Pulm Med, Hellerup, Denmark [ 4 ] Haukeland Univ Sjukehus, Dept Pulm Med, Bergen, Norway [ 5 ] Vestre Viken Hosp Trust, Drammen Hosp, Sect Oncol, Drammen, Norway Show more [ 6 ] Akershus Univ Hosp, Dept Radiol, Loerenskog, Norway Show more [ 7 ] Canc Registry Norway, Registry Dept, Oslo, Norway Show more [ 8 ] Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden [ 9 ] Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden Show more [ 10 ] Skane Univ Hosp, Dept Heart & Lung Dis, Lund, Sweden Show more [ 11 ] Karolinska Univ Hosp, Dept Thoraxradiol, Stockholm, Sweden Show more [ 12 ] Karolinska Univ Hosp, Dept Cardiothorac Surg, Stockholm, Sweden Show more [ 13 ] Turku Univ, Vaasa Oncol Clin, Turku, Finland Show more [ 14 ] Univ Helsinki, Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland Show more [ 15 ] Univ Iceland, Landspitli Univ Hosp, Dept Cardiothorac Surg, Fac Med, Reykjavik, Iceland, Department of Cardiothoracic Surgery RT Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Oncology, Finsen Centre/Rigshospitalet Copenhagen, Copenhagen, Denmark, Department of Pulmonary Medicine, Gentofte University Hospital, Hellerup, Denmark, Department of Pulmonary Medicine, Haukeland universitetssjukehus, Bergen, Norway, Section of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway, Registry Department, Cancer Registry of Norway, Oslo, Norway, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden, Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden, Department of Heart and Lung Diseases, Skåne University Hospital, Sweden, Department of Thoraxradiology, Karolinska University Hospital, Stockholm, Sweden, Department of Cardiothoracic Surgery, Karolinska University Hospital, Stockholm, Sweden, Vaasa Oncology Clinic, Turku University, Turku, Finland, Helsinki University, Helsinki University Hospital, Heart and Lung Centre, Helsinki, Finland, Department of Cardiothoracic Surgery, Faculty of Medicine, Landspitli University Hospital, University of Iceland, Reykjavik, Iceland, Pedersen, Jesper Holst, Sørensen, Jens Benn, Saghir, Zaigham, Fløtten, Øystein, Brustugun, Odd Terje, Ashraf, Haseem, Strand, Trond-Eirik, Friesland, Signe, Koyi, Hirsh, Ek, Lars, Nyrén, Sven, Bergman, Per, Jekunen, Antti, Nieminen, Eeva-Maija, Gudbjartsson, Tomas, [ 1 ] Univ Copenhagen, Dept Cardiothorac Surg, RT Rigshosp, Copenhagen, Denmark Show more [ 2 ] Rigshosp Copenhagen, Dept Oncol, Finsen Ctr, Copenhagen, Denmark Show more [ 3 ] Gentofte Univ Hosp, Dept Pulm Med, Hellerup, Denmark [ 4 ] Haukeland Univ Sjukehus, Dept Pulm Med, Bergen, Norway [ 5 ] Vestre Viken Hosp Trust, Drammen Hosp, Sect Oncol, Drammen, Norway Show more [ 6 ] Akershus Univ Hosp, Dept Radiol, Loerenskog, Norway Show more [ 7 ] Canc Registry Norway, Registry Dept, Oslo, Norway Show more [ 8 ] Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden [ 9 ] Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden Show more [ 10 ] Skane Univ Hosp, Dept Heart & Lung Dis, Lund, Sweden Show more [ 11 ] Karolinska Univ Hosp, Dept Thoraxradiol, Stockholm, Sweden Show more [ 12 ] Karolinska Univ Hosp, Dept Cardiothorac Surg, Stockholm, Sweden Show more [ 13 ] Turku Univ, Vaasa Oncol Clin, Turku, Finland Show more [ 14 ] Univ Helsinki, Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland Show more [ 15 ] Univ Iceland, Landspitli Univ Hosp, Dept Cardiothorac Surg, Fac Med, Reykjavik, Iceland, Department of Cardiothoracic Surgery RT Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, Department of Oncology, Finsen Centre/Rigshospitalet Copenhagen, Copenhagen, Denmark, Department of Pulmonary Medicine, Gentofte University Hospital, Hellerup, Denmark, Department of Pulmonary Medicine, Haukeland universitetssjukehus, Bergen, Norway, Section of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway, Registry Department, Cancer Registry of Norway, Oslo, Norway, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden, Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden, Department of Heart and Lung Diseases, Skåne University Hospital, Sweden, Department of Thoraxradiology, Karolinska University Hospital, Stockholm, Sweden, Department of Cardiothoracic Surgery, Karolinska University Hospital, Stockholm, Sweden, Vaasa Oncology Clinic, Turku University, Turku, Finland, Helsinki University, Helsinki University Hospital, Heart and Lung Centre, Helsinki, Finland, Department of Cardiothoracic Surgery, Faculty of Medicine, Landspitli University Hospital, University of Iceland, Reykjavik, Iceland, Pedersen, Jesper Holst, Sørensen, Jens Benn, Saghir, Zaigham, Fløtten, Øystein, Brustugun, Odd Terje, Ashraf, Haseem, Strand, Trond-Eirik, Friesland, Signe, Koyi, Hirsh, Ek, Lars, Nyrén, Sven, Bergman, Per, Jekunen, Antti, Nieminen, Eeva-Maija, and Gudbjartsson, Tomas
Abstract: To access publisher's full text version of this article click on the hyperlink below, INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

30. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Author: Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA deCODE Genet, Reykjavik, Iceland Aarhus Univ Hosp, Risskov, Denmark Aarhus Univ, Ctr Integrat Sequencing iSEQ, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Copenhagen, Denmark Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland Cardiff Univ, Sch Med, Ctr Psychiat Genet & Genom, MRC, Cardiff CF10 3AX, S Glam, Wales Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dublin 2, Ireland Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia Statens Serum Inst, DK-2300 Copenhagen, Denmark Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Kings Coll London, Inst Psychiat, London, England Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, DenmarkQueens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Belgrade, Fac Med, Belgrade, Serbia Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands Kings Coll London, Dept Neurosci, London, England Virginia Commonwealth Univ, Dept Human & Mol Genet, Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Kähler, Anna K, Akterin, Susanne, Bergen, Sarah E, Collins, Ann L, Crowley, James J, Fromer, Menachem, Kim, Yunjung, Bender, Stephan, Bramon, Elvira, Collier, David, Crespo-Facorro, Benedicto, Hall, Jeremy, Iyegbe, Conrad, McIntosh, Andrew, Murray, Robin M, Lee, Sang Hong, Ophoff, Roel A, Scolnick, Edward, Powell, John, Rujescu, Dan, Van Os, Jim, Walshe, Muriel, Weisbrod, Matthias, Wiersma, Durk, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Magnusson, Patrik K E, Purcell, Shaun, Brown, Matthew A, Casas, Juan P, Corvin, Aiden P, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, McCarroll, Steven A, Sanchez, Nick, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Sklar, Pamela, Freeman, Colin, Stahl, Eli A, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard D, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Hultman, Christina M, Langford, Cordelia, Hunt, Sarah E, Williams, Stephanie, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Sullivan, Patrick F, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Wray, Naomi R, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew J, Borglum, Anders D, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Xia, Kai, Bulik-Sullivan, Brendan K, McCarthy, Mark I, O'Donovan, Michael C, Bettella, Francesco, Stefansson, Kari, Cormican, Paul, Craddock, Nick, Jablensky, Assen, de Leeuw, Christiaan, Durmishi, Naser, Gill, Michael, Golimbet, Vera, Hamshere, Marian L, Holmans, Peter, Hougaard, David M, Kendler, Kenneth S, Lin, Kuang, Morris, Derek W, Kahn, Rene S, Mors, Ole, Mortensen, Preben B, Neale, Benjamin M, O'Neill, Francis A, Owen, Michael J, Milovancevic, Milica Pejovic, Posthuma, Danielle, Richards, Alexander L, Riley, Brien P, Kalaydjieva, Luba, Ruderfer, Douglas, Sigurdsson, Engilbert, Silagadze, Teimuraz, Smit, August B, Stefansson, Hreinn, Steinberg, Stacy, Suvisaari, Jaana, Tosato, Sarah, Verhage, Matthijs, Lawrie, Stephen, Walters, James T, Levinson, Douglas F, Gejman, Pablo V, Laurent, Claudine, Mowry, Bryan J, Pulver, Ann E, Lewis, Cathryn M, Schwab, Sibylle G, Wildenauer, Dieter B, Dudbridge, Frank, Shi, Jianxin, Albus, Margot, Alexander, Madeline, Campion, Dominique, Cohen, David, Dikeos, Dimitris, Duan, Jubao, Eichhammer, Peter, Godard, Stephanie, Hansen, Mark, Lerer, F Bernard, Liang, Kung-Yee, Maier, Wolfgang, Mallet, Jacques, Nertney, Deborah A, Nestadt, Gerald, Linszen, Don H, Norton, Nadine, Papadimitriou, George N, Ribble, Robert, Sanders, Alan R, Silverman, Jeremy M, Walsh, Dermot, Williams, Nigel M, Wormley, Brandon, Arranz, Maria J, Mata, Ignacio, Bakker, Steven, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA deCODE Genet, Reykjavik, Iceland Aarhus Univ Hosp, Risskov, Denmark Aarhus Univ, Ctr Integrat Sequencing iSEQ, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Copenhagen, Denmark Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland Cardiff Univ, Sch Med, Ctr Psychiat Genet & Genom, MRC, Cardiff CF10 3AX, S Glam, Wales Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dublin 2, Ireland Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia Statens Serum Inst, DK-2300 Copenhagen, Denmark Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Kings Coll London, Inst Psychiat, London, England Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, DenmarkQueens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Belgrade, Fac Med, Belgrade, Serbia Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands Kings Coll London, Dept Neurosci, London, England Virginia Commonwealth Univ, Dept Human & Mol Genet, Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Kähler, Anna K, Akterin, Susanne, Bergen, Sarah E, Collins, Ann L, Crowley, James J, Fromer, Menachem, Kim, Yunjung, Bender, Stephan, Bramon, Elvira, Collier, David, Crespo-Facorro, Benedicto, Hall, Jeremy, Iyegbe, Conrad, McIntosh, Andrew, Murray, Robin M, Lee, Sang Hong, Ophoff, Roel A, Scolnick, Edward, Powell, John, Rujescu, Dan, Van Os, Jim, Walshe, Muriel, Weisbrod, Matthias, Wiersma, Durk, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Magnusson, Patrik K E, Purcell, Shaun, Brown, Matthew A, Casas, Juan P, Corvin, Aiden P, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, McCarroll, Steven A, Sanchez, Nick, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Sklar, Pamela, Freeman, Colin, Stahl, Eli A, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard D, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Hultman, Christina M, Langford, Cordelia, Hunt, Sarah E, Williams, Stephanie, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Sullivan, Patrick F, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Wray, Naomi R, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew J, Borglum, Anders D, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Xia, Kai, Bulik-Sullivan, Brendan K, McCarthy, Mark I, O'Donovan, Michael C, Bettella, Francesco, Stefansson, Kari, Cormican, Paul, Craddock, Nick, Jablensky, Assen, de Leeuw, Christiaan, Durmishi, Naser, Gill, Michael, Golimbet, Vera, Hamshere, Marian L, Holmans, Peter, Hougaard, David M, Kendler, Kenneth S, Lin, Kuang, Morris, Derek W, Kahn, Rene S, Mors, Ole, Mortensen, Preben B, Neale, Benjamin M, O'Neill, Francis A, Owen, Michael J, Milovancevic, Milica Pejovic, Posthuma, Danielle, Richards, Alexander L, Riley, Brien P, Kalaydjieva, Luba, Ruderfer, Douglas, Sigurdsson, Engilbert, Silagadze, Teimuraz, Smit, August B, Stefansson, Hreinn, Steinberg, Stacy, Suvisaari, Jaana, Tosato, Sarah, Verhage, Matthijs, Lawrie, Stephen, Walters, James T, Levinson, Douglas F, Gejman, Pablo V, Laurent, Claudine, Mowry, Bryan J, Pulver, Ann E, Lewis, Cathryn M, Schwab, Sibylle G, Wildenauer, Dieter B, Dudbridge, Frank, Shi, Jianxin, Albus, Margot, Alexander, Madeline, Campion, Dominique, Cohen, David, Dikeos, Dimitris, Duan, Jubao, Eichhammer, Peter, Godard, Stephanie, Hansen, Mark, Lerer, F Bernard, Liang, Kung-Yee, Maier, Wolfgang, Mallet, Jacques, Nertney, Deborah A, Nestadt, Gerald, Linszen, Don H, Norton, Nadine, Papadimitriou, George N, Ribble, Robert, Sanders, Alan R, Silverman, Jeremy M, Walsh, Dermot, Williams, Nigel M, Wormley, Brandon, Arranz, Maria J, Mata, Ignacio, and Bakker, Steven
Abstract: To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field., Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

31. Protocol for the development of the international population registry for aphasia after stroke (I-PRAISE)

Author: Erin Godecke, R. Mc Menamin, M. Gil, Linda Williams, A. Lifshitz Ben Basat, Madeline Cruice, C. Mendez-Orellana, Karen Sage, Sarah J. Wallace, İlknur Maviş, K. Sprecht, Marialuisa Gandolfi, Per Östberg, Dominique A Cadilhac, L. Martinez Jiminez, H. Robson, Ann Charlotte Laska, M. Blom Johansson, R. Grima, M. van de Sandt-Koenderman, Luis M. T. Jesus, Evy Visch-Brink, Fofi Constantinidou, Marian C. Brady, Guadalupe Dávila, Tarja Kukkonen, H. Obrig, Caterina Breitenstein, Maria Kambanaros, Myzoon Ali, Marcelo L. Berthier, E. Wehling, S. Wielaert, [Ali, M.] Glasgow Caledonian Univ, NMAHP Res Unit, A433 Govan Mbeki Bldg, Glasgow G4 0BA, Lanark, Scotland, [Brady, M. C.] Glasgow Caledonian Univ, NMAHP Res Unit, A433 Govan Mbeki Bldg, Glasgow G4 0BA, Lanark, Scotland, [Ben Basat, A. Lifshitz] Ariel Univ, Dept Commun Disorders, Ariel, Israel, [Berthier, M.] Univ Malaga, Inst Invest Biomed Malaga IBIMA, Cognit Neurol & Aphasia Unit, Ctr Invest Medicosanitarias, Malaga, Spain, [Davila, G.] Univ Malaga, Inst Invest Biomed Malaga IBIMA, Cognit Neurol & Aphasia Unit, Ctr Invest Medicosanitarias, Malaga, Spain, [Blom Johansson, M.] Uppsala Univ, Dept Neurosci, Speech Language Pathol, Uppsala, Sweden, [Breitenstein, C.] Univ Munster, Dept Neurol, Inst Translat Neurol, Munster, Germany, [Cadilhac, D. A.] Monash Univ, Sch Clin Sci, Dept Med, Monash Hlth, Melbourne, Vic, Australia, [Constantinidou, F.] Univ Cyprus Nicosia, Dept Psychol, Nicosia, Cyprus, [Constantinidou, F.] Univ Cyprus Nicosia, Ctr Appl Neurosci, Nicosia, Cyprus, [Cruice, M.] City Univ London, London, England, [Davila, G.] Univ Malaga, Fac Psychol & Speech Therapy, Area Psychobiol, Malaga, Spain, [Gandolfi, M.] Univ Verona, Dept Neurosci Biomed & Movement Sci, Verona, Italy, [Gil, M.] Loewenstein Hosp & Rehabil Ctr, Dept Commun Disorders, Raanana, Israel, [Grima, R.] Univ Malta Imsida, Dept Commun Therapy, Fac Hlth Sci, Msida, Malta, [Godecke, E.] Edith Cowan Univ, Sch Med & Hlth Sci, Churchlands, WA, Australia, [Godecke, E.] Sir Charles Gairdner Hosp, Speech Pathol Dept, Nedlands, WA, Australia, [Godecke, E.] Ctr Res Excellence Aphasia Recovery & Rehabil, Melbourne, Vic, Australia, [Jesus, L.] Univ Aveiro, Sch Hlth Sci ESSUA, Aveiro, Portugal, [Jesus, L.] Univ Aveiro, Inst Elect & Informat Engn Aveiro IEETA, Aveiro, Portugal, [Jiminez, L. Martinez] Univ Talca, Talca, Chile, [Kambanaros, M.] Univ South Australia, Allied Hlth & Human Performance, Adelaide South, Australia, [Kukkonen, T.] Tampere Univ Hosp, Pirkanmaa Hosp Dist, Dept ENT Phoniatry, Tampere, Finland, [Laska, A.] Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden, [Mavis, I] Anadolu Univ, Speech & Language Therapy Dept, Eskisehir, Turkey, [Mc Menamin, R.] Natl Univ Ireland, Sch Hlth Sci, Discipline Speech & Language Therapy, Galway, Ireland, [Mendez-Orellana, C.] Pontificia Univ Catolica Chile, Fac Med, Dept Ciencias Salud, Carrera Fonoaudiol, Santiago, Chile, [Obrig, H.] Univ Hosp Leipzig, Clin Cognit Neurol, Leipzig, Germany, [Obrig, H.] MPI Human Cognit & Brain Sci, Leipzig, Germany, [Ostberg, P.] Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden, [Robson, H.] UCL, Psychol & Language Sci, London, England, [Sage, K.] Manchester Metropolitan Univ, Fac Hlth Psychol & Social Care, Dept Nursing, Manchester, Lancs, England, [Van De Sandt-koenderman, M.] Rijndam Rehabil Ctr, Dept Rehabil Med, Rotterdam, Netherlands, [Wielaert, S.] Rijndam Rehabil Ctr, Dept Rehabil Med, Rotterdam, Netherlands, [Van De Sandt-koenderman, M.] Erasmus MC, Rotterdam, Netherlands, [Wielaert, S.] Erasmus MC, Rotterdam, Netherlands, [Sprecht, K.] Univ Bergen, Fac Psychol, Dept Biol & Med Psychol, Bergen, Norway, [Visch-Brink, E.] Erasmus MC, Dept Neurol & Neurosurg, Rotterdam, Netherlands, [Wehling, E.] Haukeland Hosp, Dept Phys Med & Rehabil, Bergen, Norway, [Wallace, S. J.] Univ Queensland, Sch Hlth & Rehabil Sci, Queensland Aphasia Res Ctr, Brisbane, Qld, Australia, [Williams, L. J.] Univ Edinburgh, Usher Inst, Edinburgh, Midlothian, Scotland, Tavistock Trust for Aphasia, Ali, M, Lifshitz Ben Basat, A, Berthier, M, Blom Johansson, M, Kambanaros, M, Brady, MC, Tampere University, Department of Neurosciences and Rehabilitation, Welfare Sciences, Research & Education, Radiology & Nuclear Medicine, Neurology, Neurosurgery, Rehabilitation Medicine, and Department of Marketing Management
Subjects: Linguistics and Language, medicine.medical_specialty, data collection, 515 Psychology, medicine.medical_treatment, Population, registry, behavioral disciplines and activities, Language and Linguistics, Language assessment, Rating scale, Aphasia, Övrig annan medicin och hälsovetenskap, Developmental and Educational Psychology, medicine, Speech, Controlled-trial, protocol, Lesion, Western Aphasia Battery, education, outcome assessment, Stroke, Language, education.field_of_study, Rehabilitation, Communication, 3112 Neurosciences, Reliability, LPN and LVN, medicine.disease, Other Medical Sciences not elsewhere specified, Neurology, Otorhinolaryngology, RC0321, Physical therapy, Therapy, Neurology (clinical), medicine.symptom, Speech-Language Pathology, Psychology
Abstract: Background We require high-quality information on the current burden, the types of therapy and resources available, methods of delivery, care pathways and long-term outcomes for people with aphasia. Aim To document and inform international delivery of post-stroke aphasia treatment, to optimise recovery and reintegration of people with aphasia. Methods & Procedures Multi-centre, prospective, non-randomised, open study, employing blinded outcome assessment, where appropriate, including people with post-stroke aphasia, able to attend for 30 minutes during the initial language assessment, at first contact with a speech and language therapist for assessment of aphasia at participating sites. There is no study-mandated intervention. Assessments will occur at baseline (first contact with a speech and language therapist for aphasia assessment), discharge from Speech and Language Therapy (SLT), 6 and 12-months post-stroke. Our primary outcome is changed from baseline in the Amsterdam Nijmegen Everyday Language Test (ANELT/Scenario Test for participants with severe verbal impairments) at 12-months post-stroke. Secondary outcomes at 6 and 12 months include the Therapy Outcome Measure (TOMS), Subjective Index of Physical and Social Outcome (SIPSO), Aphasia Severity Rating Scale (ASRS), Western Aphasia Battery Aphasia Quotient (WAB-AQ), stroke and aphasia quality of life scale (SAQoL-39), European Quality of Life Scale (EQ-5D), lesion description, General Health Questionnaire (GHQ-12), resource use, and satisfaction with therapy provision and success. We will collect demography, clinical data, and therapy content. Routine neuroimaging and medication administration records will be accessed where possible; imaging will be pseudonymised and transferred to a central reading centre. Data will be collected in a central registry. We will describe demography, stroke and aphasia profiles and therapies available. International individual participant data (IPD) meta-analyses will examine treatment responder rates based on minimal detectable change & clinically important changes from baseline for primary and secondary outcomes at 6 and 12 months. Multivariable meta-analyses will examine associations between demography, therapy, medication use and outcomes, considering service characteristics. Where feasible, costs associated with treatment will be reported. Where available, we will detail brain lesion size and site, and examine correlations with SLT and language outcome at 12 months. Conclusion International differences in care, resource utilisation and outcomes will highlight avenues for further aphasia research, promote knowledge sharing and optimise aphasia rehabilitation delivery. IPD meta-analyses will enhance and expand understanding, identifying cost-effective and promising approaches to optimise rehabilitation to benefit people with aphasia.
Published: 2022
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32. Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus

Author: Alvaro Gallego-Martinez, Alba Escalera-Balsera, Natalia Trpchevska, Paula Robles-Bolivar, Pablo Roman-Naranjo, Lidia Frejo, Patricia Perez-Carpena, Jan Bulla, Silvano Gallus, Barbara Canlon, Christopher R. Cederroth, Jose A. Lopez-Escamez, [Gallego-Martinez, Alvaro] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Escalera-Balsera, Alba] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Robles-Bolivar, Paula] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Roman-Naranjo, Pablo] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Frejo, Lidia] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Perez-Carpena, Patricia] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Lopez-Escamez, Jose A. A.] Univ Granada, Ctr Genom & Oncol Res Pfizer, Dept Genom Med, Otol & Neurotol Grp CTS495,GENYO,Andalusian Reg Go, Ave Ilustrac 114, Granada 18016, Spain, [Gallego-Martinez, Alvaro] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Escalera-Balsera, Alba] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Robles-Bolivar, Paula] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Roman-Naranjo, Pablo] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Frejo, Lidia] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Perez-Carpena, Patricia] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Lopez-Escamez, Jose A. A.] Hosp Univ Virgen de las Nieves, Inst Invest Biosanit, Ibs Granada, Dept Otolaryngol, Granada 18014, Spain, [Gallego-Martinez, Alvaro] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Escalera-Balsera, Alba] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Robles-Bolivar, Paula] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Roman-Naranjo, Pablo] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Frejo, Lidia] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Perez-Carpena, Patricia] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Lopez-Escamez, Jose A. A.] CIBERER, Ctr Invest Biomed Red Enfermedades Raras, Sensorineural Pathol Programme, Madrid 28029, Spain, [Trpchevska, Natalia] Karolinska Inst, Dept Physiol & Pharmacol, Sect Expt Audiol, S-17177 Stockholm, Sweden, [Canlon, Barbara] Karolinska Inst, Dept Physiol & Pharmacol, Sect Expt Audiol, S-17177 Stockholm, Sweden, [Cederroth, Christopher R. R.] Karolinska Inst, Dept Physiol & Pharmacol, Sect Expt Audiol, S-17177 Stockholm, Sweden, [Perez-Carpena, Patricia] Univ Granada, Dept Surg, Div Otolaryngol, Granada 18016, Spain, [Lopez-Escamez, Jose A. A.] Univ Granada, Dept Surg, Div Otolaryngol, Granada 18016, Spain, [Bulla, Jan] Univ Bergen, Dept Math, N-5020 Bergen, Norway, [Bulla, Jan] Univ Regensburg, Dept Psychiat & Psychotherapy, D-93053 Regensburg, Germany, [Gallus, Silvano] Ist Ric Farmacol Mario Negri IRCCS, Dept Environm Hlth Sci, I-20156 Milan, Italy, [Cederroth, Christopher R. R.] Nottingham Univ Hosp NHS Trust, Natl Inst Hlth Res NIHR, Nottingham Biomed Res Ctr, Ropewalk House, Nottingham NG1 5DU, England, [Cederroth, Christopher R. R.] Univ Nottingham, Sch Med, Div Clin Neurosci, Hearing Sci, Nottingham NG7 2UH, England, 'La Caixa' Foundation, European Union, Svenska Lakaresalskapet, Hoerselforskningsfonden, Tysta Skolan and Forschung Fuer Leben, Andalusian Goverment (CECEU), Sara Borrell postdoctoral Fellowship (ISCIII), Andalusian Health Government (CSyF 2020 POSTDOC), and Swedish Research Council
Subjects: Association, Standards, Medical genetics, Framework, Genetics, Mechanisms, American-college, Joint consensus recommendation, Mammalian homolog, Guidelines, Structural variants, Molecular Biology, Genetics (clinical)
Abstract: Tinnitus is the phantom percept of an internal non-verbal set of noises and tones. It is reported by 15% of the population and it is usually associated with hearing and/or brain disorders. The role of structural variants (SVs) in coding and non-coding regions has not been investigated in patients with severe tinnitus. In this study, we performed whole-genome sequencing in 97 unrelated Swedish individuals with chronic tinnitus (TIGER cohort). Rare single nucleotide variants (SNV), large structural variants (LSV), and copy number variations (CNV) were retrieved to perform a gene enrichment analysis in TIGER and in a subgroup of patients with severe tinnitus (SEVTIN, n = 34), according to the tinnitus handicap inventory (THI) scores. An independent exome sequencing dataset of 147 Swedish tinnitus patients was used as a replication cohort (JAGUAR cohort) and population-specific datasets from Sweden (SweGen) and Non-Finish Europeans (NFE) from gnomAD were used as control groups. SEVTIN patients showed a higher prevalence of hyperacusis, hearing loss, and anxiety when they were compared to individuals in the TIGER cohort. We found an enrichment of rare missense variants in 6 and 8 high-constraint genes in SEVTIN and TIGER cohorts, respectively. Of note, an enrichment of missense variants was found in the CACNA1E gene in both SEVTIN and TIGER. We replicated the burden of missense variants in 9 high-constrained genes in the JAGUAR cohort, including the gene NAV2, when data were compared with NFE. Moreover, LSVs in constrained regions overlapping CACNA1E, NAV2, and TMEM132D genes were observed in TIGER and SEVTIN., La Caixa Foundation GNP-182 100010434 LCF/PR/DE18/52010002 H2020-SC1-2019-848261, European Commission 848261 722046, Svenska Lakaresalskapet SLS-779681 Hoerselforskningsfonden 503 Tysta Skolan and Forschung Fuer Leben, Andalusian Goverment (CECEU) DOC_01677, Sara Borrell postdoctoral Fellowship (ISCIII) CD20/00153, Andalusian Health Government (CSyF 2020 POSTDOC) RH-0150-2020, Swedish Research Council, European Commission 2018-05973
Published: 2022

33. Structural basis of the human endoglin-BMP9 interaction: Insights into BMP signaling and HHT1

Author: Takako, Saito, Marcel, Bokhove, Romina, Croci, Sara, Zamora-Caballero, Ling, Han, Michelle, Letarte, Daniele, de Sanctis, Luca, Jovine, Karolinska Inst, Ctr Innovat Med, S-14183 Huddinge, Sweden, Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden, Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Cell Sci, Fukushima 9601295, Japan, Univ Toronto, Dept Immunol, Toronto, ON M5G 0A4, Canada, Univ Toronto, Hosp Sick Children, Peter Gilgan Ctr Res & Learning, Mol Med, Toronto, ON M5G 0A4, Canada, and European Synchrotron Radiation Facility (ESRF)
Subjects: Models, Molecular, Activin Receptors, Type II, [SDV]Life Sciences [q-bio], orphan domain, Crystallography, X-Ray, Ligands, Protein Structure, Secondary, Article, Structure-Activity Relationship, Protein Domains, Gene Duplication, Humans, hereditary hemorrhagic telangiectasia, protein interaction domains and motifs, Disulfides, lcsh:QH301-705.5, x-ray crystallography, endoglin, zona pellucida domain, bone morphogenetic protein receptors, cell surface receptors, TGF-β superfamily proteins, growth differentiation factor 2, Kinetics, lcsh:Biology (General), Telangiectasia, Hereditary Hemorrhagic, Protein Multimerization, Hydrophobic and Hydrophilic Interactions, Protein Binding, Signal Transduction
Abstract: Summary Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway., Graphical Abstract, Highlights • Crystal structures of human ENG and its complex with BMP9 were determined • The orphan domain of ENG adopts a fold that explains the effect of HHT1 mutations • ZP module-mediated dimerization of ENG creates a clamp that secures homodimeric BMP9 • ENG-bound BMP9 can interact with the ALK1 receptor but not the ActRIIB receptor, Endoglin (ENG)/CD105, a key player in angiogenesis and vascular homeostasis, is mutated in the genetic disorder HHT1 and implicated in tumor angiogenesis and preeclampsia. Saito et al. determine structures of human ENG alone and in complex with the physiological ligand BMP9, shedding light onto the molecular basis of BMP signaling.
Published: 2017
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34. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 4 ] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA [ 5 ] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway [ 6 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy [ 7 ] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA [ 8 ] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA [ 9 ] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA [ 10 ] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland [ 11 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 12 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 13 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada [ 14 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 15 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA [ 16 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany [ 17 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 18 ] Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden [ 19 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 20 ] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 21 ] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland [ 22 ] Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany [ 23 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany [ 24 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain [ 25 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain [ 26 ] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain [ 27 ] NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA [ 28 ] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland [ 29 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 30 ] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany [ 31 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark [ 32 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany [ 33 ] Univ Tubingen, D-72074 Tubingen, Germany [ 34 ] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany [ 35 ] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany [ 36 ] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany [ 37 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA [ 38 ] IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain [ 39 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy [ 40 ] Univ Hosp Pisa, I-56126 Pisa, Italy [ 41 ] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany [ 42 ] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW 2145, Australia [ 43 ] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany [ 44 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA [ 45 ] Columbia Univ, Dept Pediat, New York, NY 10032 USA [ 46 ] Columbia Univ, Dept Med, New York, NY 10032 USA [ 47 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 48 ] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England [ 49 ] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England [ 50 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 51 ] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA [ 52 ] Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France [ 53 ] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands [ 54 ] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands [ 55 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain [ 56 ] Univ Autonoma Barcelona, Barcelona 08035, Spain [ 57 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 58 ] CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 59 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA [ 60 ] Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa [ 61 ] Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England [ 62 ] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada [ 63 ] Univ Laval, Quebec City, PQ G1V 4G2, Canada [ 64 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 65 ] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England [ 66 ] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden [ 67 ] Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden [ 68 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany [ 69 ] Comprehens Canc Ctr EMN, D-91054 Erlangen, Germany [ 70 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 71 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 72 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 73 ] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany [ 74 ] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany [ 75 ] German Canc Res Ctr, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany [ 76 ] Lund Univ, Ctr Primary Hlth Care Res, SE-22100 Malmo, Sweden [ 77 ] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece [ 78 ] McGill Univ, Program Canc Genet, Montreal, PQ H3A 0G4, Canada [ 79 ] Univ Philadelphia, Philadelphia, PA 19104 USA [ 80 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 81 ] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA [ 82 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, Los Angeles, CA 90095 USA [ 83 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA [ 84 ] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA [ 85 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02215 USA [ 86 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA [ 87 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark [ 88 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia [ 89 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66205 USA [ 90 ] McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada [ 91 ] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H4A 3J1, Canada [ 92 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA [ 93 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain [ 94 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, F-70115 Villejuif, France [ 97 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England [ 98 ] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 99 ] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany [ 100 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark [ 101 ] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia [ 102 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 103 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA [ 104 ] Netherlands Canc Inst, Family Canc Clin, NL-1000 BE Amsterdam, Netherlands [ 105 ] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 106 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 107 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia [ 108 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 109 ] NN Petrov Oncol Res Inst, St Petersburg 197758, Russia [ 110 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA [ 111 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 8006, Australia [ 112 ] Univ Melbourne, Dept Oncol, Melbourne, Vic 8006, Australia [ 113 ] State Res Inst, Ctr Innovat Med, LT-08661 Vilnius, Lithuania [ 114 ] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark [ 115 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 116 ] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England [ 117 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland [ 119 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 120 ] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England [ 121 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 122 ] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany [ 123 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland [ 124 ] Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong Sanat & Hosp, Hong Kong, Hong Kong, Peoples R China [ 125 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 126 ] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium [ 127 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain [ 128 ] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA [ 129 ] Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA [ 130 ] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden [ 131 ] Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA [ 132 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 133 ] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore [ 134 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 135 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 136 ] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA [ 137 ] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA [ 138 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 139 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany [ 140 ] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA [ 141 ] Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA [ 142 ] Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada [ 143 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 144 ] Invitae Corp, San Francisco, CA 94107 USA [ 145 ] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA [ 146 ] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary [ 147 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 148 ] Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea [ 149 ] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea [ 150 ] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands [ 151 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England [ 152 ] Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy [ 153 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 154 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 155 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 156 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland [ 157 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 158 ] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England [ 159 ] Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden [ 160 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 161 ] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel [ 162 ] Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel [ 163 ] B Rappaport Fac Med, IL-34362 Haifa, Israel [ 164 ] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA [ 165 ] Int Agcy Res Canc, F-69008 Lyon, France [ 166 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands [ 167 ] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain [ 168 ] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain [ 169 ] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA [ 170 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 171 ] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany [ 172 ] Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany [ 173 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 174 ] John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia [ 175 ] Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA [ 176 ] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada [ 177 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France [ 178 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 179 ] Hannover Med Sch, D-30625 Hannover, Germany [ 180 ] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden [ 181 ] Inst Curie, Dept Tumour Biol, F-75248 Paris, France [ 182 ] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France [ 183 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 184 ] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal [ 185 ] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal [ 186 ] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia [ 187 ] Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands [ 201 ] Charite, Inst Human Genet, D-13353 Berlin, Germany [ 202 ] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [ 203 ] Univ Hosp Ulm, D-89075 Ulm, Germany [ 204 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [ 205 ] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland [ 206 ] Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA [ 207 ] Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium [ 208 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 209 ] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain [ 210 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 211 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia [ 212 ] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA
Subjects: 0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.
Published: 2018
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35. Innovations in Doctoral Training and Research on Tinnitus: The European School on Interdisciplinary Tinnitus Research (ESIT) Perspective

Author: Winfried Schlee, Deborah A. Hall, Barbara Canlon, Rilana F. F. Cima, Emile de Kleine, Franz Hauck, Alex Huber, Silvano Gallus, Tobias Kleinjung, Theodore Kypraios, Berthold Langguth, José A. Lopez-Escamez, Alessandra Lugo, Martin Meyer, Marzena Mielczarek, Arnaud Norena, Flurin Pfiffner, Rüdiger C. Pryss, Manfred Reichert, Teresa Requena, Martin Schecklmann, Pim van Dijk, Paul van de Heyning, Nathan Weisz, Christopher R. Cederroth, University of Regensburg, Nottingham Digestive Diseases Centre: NIHR Biomedical Research Unit, Nottingham University Hospitals NHS Trust (NUH), Karolinska Institutet [Stockholm], Maastricht University [Maastricht], University Medical Center Groningen [Groningen] (UMCG), Universität Ulm - Ulm University [Ulm, Allemagne], University hospital of Zurich [Zurich], Istituto di Ricerche Farmacologiche 'Mario Negri', 20156 Milan, Universidad de Granada = University of Granada (UGR), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], SPRU, Medical University of Łódź (MUL), Neurosciences sensorielles et cognitives (NSC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Groningen [Groningen], Brain Research centre Antwerp for Innovative and Interdisciplinary Neuromodulation (BRAI²N), Antwerp University Hospital [Edegem] (UZA), Processus mentaux et activation cérébrale, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR19-Institut National de la Santé et de la Recherche Médicale (INSERM), Nottingham University Hospitals NHS Trust, Universidad de Granada (UGR), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Section Experimental Health Psychology, RS: FPN CPS I, University of Zurich, Cederroth, Christopher R, Perceptual and Cognitive Neuroscience (PCN), [Schlee, Winfried] Univ Regensburg, Dept Psychiat & Psychotherapy, Bezirksklinikum Regensburg, Regensburg, Germany, [Langguth, Berthold] Univ Regensburg, Dept Psychiat & Psychotherapy, Bezirksklinikum Regensburg, Regensburg, Germany, [Schecklmann, Martin] Univ Regensburg, Dept Psychiat & Psychotherapy, Bezirksklinikum Regensburg, Regensburg, Germany, [Hall, Deborah A.] NIHR Nottingham Hearing Biomed Res Ctr, Nottingham, England, [Kypraios, Theodore] NIHR Nottingham Hearing Biomed Res Ctr, Nottingham, England, [Hall, Deborah A.] Univ Nottingham, Sch Med, Div Clin Neurosci, Otol & Hearing Grp, Nottingham, England, [Canlon, Barbara] Karolinska Inst, Sect Expt Audiol, Dept Physiol & Pharmacol, Stockholm, Sweden, [Cederroth, Christopher R.] Karolinska Inst, Sect Expt Audiol, Dept Physiol & Pharmacol, Stockholm, Sweden, [Cima, Rilana F. F.] Maastricht Univ, Fac Psychol & Neurosci, Clin Psychol Sci, Maastricht, Netherlands, [de Kleine, Emile] Univ Groningen, Univ Med Ctr Groningen, Dept Otorhinolaryngol Head & Neck Surg, Groningen, Netherlands, [van Dijk, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Otorhinolaryngol Head & Neck Surg, Groningen, Netherlands, [Hauck, Franz] Ulm Univ, Inst Distributed Syst, Ulm, Germany, [Huber, Alex] Univ Zurich, Univ Hosp Zurich, Dept Otorhinolaryngol Head & Neck Surg, Zurich, Switzerland, [Kleinjung, Tobias] Univ Zurich, Univ Hosp Zurich, Dept Otorhinolaryngol Head & Neck Surg, Zurich, Switzerland, [Pfiffner, Flurin] Univ Zurich, Univ Hosp Zurich, Dept Otorhinolaryngol Head & Neck Surg, Zurich, Switzerland, [Gallus, Silvano] IRCCS Ist Ric Farmacol Mario Negri, Dept Environm Hlth Sci, Milan, Italy, [Lugo, Alessandra] IRCCS Ist Ric Farmacol Mario Negri, Dept Environm Hlth Sci, Milan, Italy, [Lopez-Escamez, Jose A.] Univ Granada, Ctr Pfizer, Dept Genom Med, Otol & Neurotol Grp,Junta Andalucia Genom & Inves, Granada, Spain, [Requena, Teresa] Univ Granada, Ctr Pfizer, Dept Genom Med, Otol & Neurotol Grp,Junta Andalucia Genom & Inves, Granada, Spain, [Lopez-Escamez, Jose A.] Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Hosp Univ Virgen de las Nieves, Dept Otolaryngol, Granada, Spain, [Meyer, Martin] Univ Zurich, Dept Psychol, Neuroplast & Learning Hlth Aging Brain HAB LAB, Zurich, Switzerland, [Mielczarek, Marzena] Med Univ Lodz, Dept Otolaryngol Laryngol Oncol Audiol & Phoniatr, Lodz, Poland, [Norena, Arnaud] Aix Marseille Univ, CNRS, Marseille, France, [Pryss, Ruediger C.] Ulm Univ, Inst Databases & Informat Syst, Ulm, Germany, [Reichert, Manfred] Ulm Univ, Inst Databases & Informat Syst, Ulm, Germany, [van de Heyning, Paul] Univ Antwerp, Antwerp Univ Hosp, Dept ORL & Head & Neck Surg, Antwerp, Belgium, [Weisz, Nathan] Univ Salzburg, Div Physiol Psychol, Ctr Cognit Neurosci, Salzburg, Austria, and European Union's Horizon research and innovation programme under the Marie Sklodowska-Curie grant
Subjects: 2805 Cognitive Neuroscience, Aging, medicine.medical_specialty, Cognitive Neuroscience, MEDLINE, 10045 Clinic for Otorhinolaryngology, medical, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Resource (project management), 1302 Aging, Multidisciplinary approach, medicine, Adults, 030212 general & internal medicine, PhD studentship, tinnitus, Curriculum, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Medical education, education, 10093 Institute of Psychology, Public health, [SCCO.NEUR]Cognitive science/Neuroscience, Perspective (graphical), ADULTS, 3. Good health, Work (electrical), hearing, Perspective, Human medicine, medicine.symptom, Psychology, 150 Psychology, heterogeneity of tinnitus, 030217 neurology & neurosurgery, Tinnitus, Neuroscience
Abstract: Tinnitus is a common medical condition which interfaces many different disciplines, yet it is not a priority for any individual discipline. A change in its scientific understanding and clinical management requires a shift toward multidisciplinary cooperation, not only in research but also in training. The European School for Interdisciplinary Tinnitus research (ESIT) brings together a unique multidisciplinary consortium of clinical practitioners, academic researchers, commercial partners, patient organizations, and public health experts to conduct innovative research and train the next generation of tinnitus researchers. ESIT supports fundamental science and clinical research projects in order to: (1) advancing new treatment solutions for tinnitus, (2) improving existing treatment paradigms, (3) developing innovative research methods, (4) performing genetic studies on, (5) collecting epidemiological data to create new knowledge about prevalence and risk factors, (6) establishing a pan-European data resource. All research projects involve inter-sectoral partnerships through practical training, quite unlike anything that can be offered by any single university alone. Likewise, the postgraduate training curriculum fosters a deep knowledge about tinnitus whilst nurturing transferable competencies in personal qualities and approaches needed to be an effective researcher, knowledge of the standards, requirements and professionalism to do research, and skills to work with others and to ensure the wider impact of research. ESIT is the seed for future generations of creative, entrepreneurial, and innovative researchers, trained to master the upcoming challenges in the tinnitus field, to implement sustained changes in prevention and clinical management of tinnitus, and to shape doctoral education in tinnitus for the future.
Published: 2018
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36. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author: Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. Samad Shera, Bernhard OBoehm, Jason Carey, Augustine Kong, Twee Hee Ong, Philippe M. Frossard, Donald W. Bowden, Toshimasa Yamauchi, Steve E. Humphries, Cordelia Langford, Xinzhong Li, Hiroshi Ikegami, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Debashish Das, John Beilby, Robin Young, Christian Herder, Asif Rasheed, Neil Robertson, Raimund Erbel, Fumihiko Takeuchi, Markku Laakso, Esteban J. Parra, Panos Deloukas, Eric Boerwinkle, Adan Valladares-Salgado, Chien-Hsiun Chen, Kay-Tee Khaw, Damiano Baldassarre, Ashok Kumar, E. Shyong Tai, Peter S. Chines, Dharambir KSanghera, Peter Donnelly, [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Natl Inst Hlth, Ctr Genome Sci, Gangoe Myeon, Yeonje Ri, South Korea [ 3 ] Univ London Imperial Coll Sci Technol & Med, London, England [ 4 ] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA [ 5 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England [ 6 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 7 ] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA [ 8 ] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA [ 9 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England [ 10 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England [ 11 ] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan [ 12 ] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore [ 13 ] Wellcome Trust Sanger Inst, Cambridge, England [ 14 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 15 ] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA [ 16 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 17 ] Univ Eastern Finland, Inst Biomed, Kuopio, Finland [ 18 ] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore [ 19 ] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore [ 20 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 21 ] Univ Milan, Dept Pharmacol Sci, Milan, Italy [ 22 ] INSERM, Ctr Rech Epidemiol & Sante Populat CESP, U1018, Villejuif, France [ 23 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 24 ] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Shanghai 200030, Peoples R China [ 25 ] Univ Birmingham, Coll Med & Dent Sci, Birmingham, W Midlands, England [ 26 ] Heart England Natl Hlth Serv NHS Fdn Trust, Ctr Biomed Res, Birmingham, W Midlands, England [ 27 ] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England [ 28 ] Addenbrookes Hosp, Inst Metab Sci, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 29 ] Baqai Inst Diabetol & Endocrinol, Karachi, Pakistan [ 30 ] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA [ 31 ] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia [ 32 ] Queen Elizabeth II Med Ctr, PathWest Lab Med Western Australia, Nedlands, WA, Australia [ 33 ] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia [ 34 ] Univ Chicago, Dept Med, Chicago, IL 60637 USA [ 35 ] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA [ 36 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 37 ] Landspitali Univ Hosp, Reykjavik, Iceland [ 38 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 39 ] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Dept Internal Med, Ulm, Germany [ 40 ] Nanyang Technol Univ, Lee Kong Chian LKC 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MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England [ 81 ] Iceland Heart Assoc, Kopavogur, Iceland [ 82 ] Univ Duisburg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 83 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 84 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 85 ] Univ Helsinki, Gen Hosp, Unit Gen Practice, Helsinki, Finland [ 86 ] Folkhalsan Res Ctr, Helsinki, Finland [ 87 ] Inst Mexicano Seguro Social, Hosp Gen Reg 1, Unidad Invest Epidemiol Clin, Mexico City, DF, Mexico [ 88 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 89 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 90 ] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA [ 91 ] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA [ 92 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 93 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 94 ] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA [ 95 ] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England [ 96 ] Vaasa Hlth Care Ctr, Vaasa, Finland [ 97 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 98 ] Harvard Univ, Sch Med, Boston, MA USA [ 99 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 100 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 101 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 102 ] Karolinska Univ, Hosp Solna, Ctr Mol Med, Stockholm, Sweden [ 103 ] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany [ 104 ] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 105 ] Univ Munich, Clin Cooperat Grp Diabet, Munich, Germany [ 106 ] Helmholtz Zentrum Muenchen, Munich, Germany [ 107 ] Tech Univ Munich, Clin Cooperat Grp Nutrigen & Type Diabet 2, Munich, Germany [ 108 ] German Ctr Diabet Res DZD, Neuherberg, Germany [ 109 ] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England [ 110 ] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo, Japan [ 111 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 112 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 113 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway [ 114 ] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands [ 115 ] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA [ 116 ] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia [ 117 ] UCL, Inst Cardiovasc Sci, London, England [ 118 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA [ 119 ] Kinki Univ, Sch Med, Dept Diabet Endocrinol & Metab, Osaka 589, Japan [ 120 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 121 ] Univ Uppsala Hosp, Dept Mol Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 122 ] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan [ 123 ] Dept Social Serv & Hlth Care, Pietarsaari, Finland [ 124 ] Aga Khan Univ, Dept Med, Karachi, Pakistan [ 125 ] Queen Elizabeth II Med Ctr, West Australian Sleep Disorders Res Inst, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia [ 126 ] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia [ 127 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 128 ] Heart & Diabet Inst, Baker Int Diabet Inst IDI, Melbourne, Australia [ 129 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 130 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 131 ] Natl Ctr Global Hlth & Med, Res Inst, Shinjuku Ku, Tokyo, Japan [ 132 ] Univ Colombo, Dept Clin Med, Diabet Res Unit, Colombo, Sri Lanka [ 133 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 134 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 135 ] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore [ 136 ] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea [ 137 ] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea [ 138 ] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland [ 139 ] deCODE Genet, Reykjavik, Iceland [ 140 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 141 ] Minist Hlth, Port Louis, Mauritius [ 142 ] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada [ 143 ] Fdn IMSS, Mexico City, DF, Mexico [ 144 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 145 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 146 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 147 ] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia [ 148 ] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines [ 149 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia [ 165 ] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan [ 166 ] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan [ 167 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 168 ] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan [ 169 ] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England [ 170 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 171 ] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea [ 172 ] Seoul Natl Univ, Coll Med, Seoul, South Korea [ 173 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 174 ] Inst Mol Med Finland FIMM, Helsinki, Finland [ 175 ] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany [ 176 ] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka [ 177 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 178 ] Univ Gen Hosp Attikon, Athens, Greece [ 179 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany [ 180 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 181 ] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA [ 182 ] Partners Ctr Personalized Genom Med, Boston, MA USA [ 183 ] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 184 ] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany [ 185 ] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA [ 186 ] MIT, Boston, MA USA [ 187 ] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA [ 188 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 189 ] Finnish Diabet Assoc, Tampere, Finland [ 190 ] Pirkanmaa Hosp Dist, Tampere, Finland [ 191 ] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology
Subjects: CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413
Published: 2014
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37. Structural Basis of Egg Coat-Sperm Recognition at Fertilization

Author: Raj, I., Al Hosseini, H.S., Dioguardi, E., Nishimura, K., Han, L., Villa, A., De Sanctis, D., Jovine, L., Karolinska Inst, Ctr Innovat Med, SE-14183 Huddinge, Sweden, Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden, and European Synchrotron Radiation Facility (ESRF)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Recognition between sperm and the egg surface marks the beginning of life in all sexually reproducing organisms. This fundamental biological event depends on the species-specific interaction between rapidly evolving counterpart molecules on the gametes. We report biochemical, crystallographic, and mutational studies of domain repeats 1-3 of invertebrate egg coat protein VERL and their interaction with cognate sperm protein lysin. VERL repeats fold like the functionally essential N-terminal repeat of mammalian sperm receptor ZP2, whose structure is also described here. Whereas sequence-divergent repeat 1 does not bind lysin, repeat 3 binds it non-species specifically via a high-affinity, largely hydrophobic interface. Due to its intermediate binding affinity, repeat 2 selectively interacts with lysin from the same species. Exposure of a highly positively charged surface of VERL-bound lysin suggests that complex formation both disrupts the organization of egg coat filaments and triggers their electrostatic repulsion, thereby opening a hole for sperm penetration and fusion
Published: 2017
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38. Escherichia coli: an old friend with new tidings

Author: Vila, J., Saez-Lopez, E., Johnson, J. R., Romling, U., Dobrindt, U., Canton, R., Giske, C. G., Naas, T., Carattoli, A., Martinez-Medina, M., Bosch, J., Retamar, P., Rodriguez-Bano, J., Baquero, F., Soto, S. M., [Vila, J.] Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona 08036, Spain, [Saez-Lopez, E.] Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona 08036, Spain, [Bosch, J.] Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona 08036, Spain, [Soto, S. M.] Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona 08036, Spain, [Vila, J.] Univ Barcelona, Hosp Clin, Dept Clin Microbiol, E-08036 Barcelona, Spain, [Bosch, J.] Univ Barcelona, Hosp Clin, Dept Clin Microbiol, E-08036 Barcelona, Spain, [Vila, J.] Inst Salud Carlos III, Spanish Network Res Infect Dis REIPI, Madrid 28220, Spain, [Canton, R.] Inst Salud Carlos III, Spanish Network Res Infect Dis REIPI, Madrid 28220, Spain, [Rodriguez-Bano, J.] Inst Salud Carlos III, Spanish Network Res Infect Dis REIPI, Madrid 28220, Spain, [Johnson, J. R.] VA Med Ctr, Minneapolis, MN USA, [Johnson, J. R.] Univ Minnesota, Minneapolis, MN 55417 USA, [Romling, U.] Karolinska Inst, S-17177 Stockholm, Sweden, [Giske, C. G.] Karolinska Inst, S-17177 Stockholm, Sweden, [Dobrindt, U.] Univ Munster, Inst Hyg, D-48149 Munster, Germany, [Canton, R.] Hosp Univ Ramon y Cajal, Microbiol Serv, E-28034 Madrid, Spain, [Baquero, F.] Hosp Univ Ramon y Cajal, Microbiol Serv, E-28034 Madrid, Spain, [Canton, R.] Inst Invest Sanitaria IRYCIS, E-28034 Madrid, Spain, [Baquero, F.] Inst Invest Sanitaria IRYCIS, E-28034 Madrid, Spain, [Naas, T.] Univ Paris 11, Hop Bicetre, F-94270 Le Kremlin Bicetre, France, [Carattoli, A.] Ist Super Sanita, Dept Infect Parasit & Immune Mediated Dis, I-00161 Rome, Italy, [Martinez-Medina, M.] Univ Girona, Dept Biol, Lab Mol Microbiol, Girona 17004, Spain, [Retamar, P.] Univ Seville, Dept Med, Hosp Univ Virgen Macarena & Virgen del Rocio, Unidad Clin Enfermedades Infecciosas Microbiol &, Seville 41071, Spain, [Rodriguez-Bano, J.] Univ Seville, Dept Med, Hosp Univ Virgen Macarena & Virgen del Rocio, Unidad Clin Enfermedades Infecciosas Microbiol &, Seville 41071, Spain, 'Instituto de Salud Carlos III' of Spain - European Development Regional Fund, Ministerio de Economia y Competitividad, Spanish Network for the Research in Infectious Diseases, Karolinska Institutet's 'Elitforskartjanst' in Molecular Microbiology, German Federal Ministry for Education and Research, and Veterans Affairs
Subjects: Cyclic-di-gmp, Onset neonatal sepsis, pathogenesis, Klebsiella-pneumoniae, Invasive e. coli, clinical, Gram-negative organisms, In-vitro activity, Carbapenemase-producing enterobacteriaceae, Spectrum-beta-lactamase, evolution, Escherichia coli, epidemiology, antimicrobial resistance, Blood-stream infections, Comparative genomic analysis
Abstract: Escherichia coli is one of the most-studied microorganisms worldwide but its characteristics are continually changing. Extraintestinal E. coli infections, such as urinary tract infections and neonatal sepsis, represent a huge public health problem. They are caused mainly by specialized extraintestinal pathogenic E. coli (ExPEC) strains that can innocuously colonize human hosts but can also cause disease upon entering a normally sterile body site. The virulence capability of such strains is determined by a combination of distinctive accessory traits, called virulence factors, in conjunction with their distinctive phylogenetic background. It is conceivable that by developing interventions against the most successful ExPEC lineages or their key virulence/colonization factors the associated burden of disease and health care costs could foreseeably be reduced in the future. On the other hand, one important problem worldwide is the increase of antimicrobial resistance shown by bacteria. As underscored in the last WHO global report, within a wide range of infectious agents including E. coli, antimicrobial resistance has reached an extremely worrisome situation that 'threatens the achievements of modern medicine'. In the present review, an update of the knowledge about the pathogenicity, antimicrobial resistance and clinical aspects of this 'old friend' was presented.New knowledgements about pathogenesis, antimicrobial resistance and clinical aspects of Escherichia coli.New knowledgements about pathogenesis, antimicrobial resistance and clinical aspects of Escherichia coli.
Published: 2016

39. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study

Author: Gregson, J, Tang, M, Ndembi, N, Hamers, Rl, Marconi, Vc, Brooks, K, Theys, K, Arruda, M, Garcia, F, Monge, S, Kanki, Pj, Kumarasamy, N, Kerschberger, B, Mor, O, Charpentier, C, Todesco, E, Rokx, C, Gras, L, Halvas, Ek, Sunpath, H, Carlo, Dd, Antinori, A, Andreoni, M, Latini, A, Mussini, C, Aghokeng, A, Sonnerborg, A, Neogi, U, Fessel, Wj, Agolory, S, Yang, C, Blanco, Jl, Juma, Jm, Smit, E, Schmidt, D, Watera, C, Asio, J, Kirungi, W, Tostevin, A, Clumeck, N, Goedhals, D, Bester, Pa, Sabin, C, Mukui, I, Santoro, M, Perno, Cf, Hunt, G, Morris, L, Pillay, D, Schulter, E, Reyes-Teran, G, Romero, K, Avila-Rios, S, Sirivichayakul, S, Ruxrungtham, K, Mekprasan, S, Dunn, D, Kaleebu, P, Raizes, E, Kantor, R, Gupta, Rk, Rhee, S, Shafer, Rw, de Wit, Tfr, Diero, L, Camacho, R, Gunthard, Hf, Hoffmann, Cj, Di Carlo, D, El-Hay, T, van Vuuren, C, de Oliveira, T, Murakami-Ogasawara, A, [Pillay, Deenan] UCL, Dept Infect, London WC1E 6BT, England, [Gupta, Ravindra K.] UCL, Dept Infect, London WC1E 6BT, England, [Tang, Michele] Stanford Univ, Dept Med, Stanford, CA 94305 USA, [Rhee, Soo-Yon] Stanford Univ, Dept Med, Stanford, CA 94305 USA, [Shafer, Robert W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA, [Gregson, John] London Sch Hyg & Trop Med, Dept Stat, London, England, [Ndembi, Nicaise] Inst Human Virol Nigeria, Abuja, Federal Capital, Nigeria, [Hamers, Raph L.] Univ Amsterdam, Acad Med Ctr, Amsterdam Inst Global Hlth & Dev, Dept Global Hlth, NL-1012 WX Amsterdam, Netherlands, [de Wit, Tobias F. Rinke] Univ Amsterdam, Acad Med Ctr, Amsterdam Inst Global Hlth & Dev, Dept Global Hlth, NL-1012 WX Amsterdam, Netherlands, [Hamers, Raph L.] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, NL-1012 WX Amsterdam, Netherlands, [de Wit, Tobias F. Rinke] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, NL-1012 WX Amsterdam, Netherlands, [Marconi, Vincent C.] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA, [Marconi, Vincent C.] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA, [Diero, Lameck] Moi Univ, Eldoret, Kenya, [Diero, Lameck] Acad Model Providing Access Healthcare, Eldoret, Kenya, [Brooks, Katherine] Brown Univ, Alpert Med Sch, Div Infect Dis, Providence, RI 02912 USA, [Theys, Kristof] KU Leuven Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium, [Camacho, Ricardo] KU Leuven Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium, [Kantor, Rami] KU Leuven Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium, [Arruda, Monica] Univ Fed Rio de Janeiro, Inst Biol, LVM, BR-21941 Rio De Janeiro, Brazil, [Garcia, Frederico] Complejo Hosp Univ Granada, Granada, Spain, Univ Alcala de Henares, E-28871 Alcala De Henares, Spain, [Monge, Susana] CIBERESP, Madrid, Spain, [Gunthard, Huldrych F.] Univ Zurich, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland, [Gunthard, Huldrych F.] Univ Zurich, Inst Med Virol, Zurich, Switzerland, [Hoffmann, Christopher J.] Johns Hopkins Univ, Baltimore, MD USA, [Hoffmann, Christopher J.] Aurum Inst, Johannesburg, South Africa, [Kanki, Phyllis J.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA, [Kumarasamy, Nagalingeshwaran] VHS, YRGCARE Med Ctr, Chennai, Tamil Nadu, India, [Kerschberger, Bernard] Med Sans Frontieres Operat Ctr Geneva, Mbabane, Eswatini, [Mor, Orna] Israel Minist Hlth, Publ Hlth Serv, Cent Virol Lab, Jerusalem, Israel, [Charpentier, Charlotte] Univ Paris Diderot, Sorbonne Paris Cite, IAME, UMR 1137, Paris, France, [Charpentier, Charlotte] INSERM, IAME, UMR 1137, Paris, France, [Charpentier, Charlotte] Hop Bichat Claude Bernard, AP HP, Virol Lab, F-75018 Paris, France, [Todesco, Eva] Hop La Pitie Salpetriere, Lab Virol, Paris, France, [Rokx, Casper] Erasmus Univ, Med Ctr, Dept Internal Med Infect Dis, Rotterdam, Netherlands, [Gras, Luuk] Stichting HIV Monitoring, Amsterdam, Netherlands, [Halvas, Elias K.] Univ Pittsburgh, Pittsburgh, PA USA, [Sunpath, Henry] Ethekwini Dist Hlth Off, Kwa Zulu, South Africa, [Di Carlo, Domenico] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy, [Santoro, Maria M.] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy, [Antinori, Antonio] INMI L Spallanzani, Infect Dis Unit, Rome, Italy, [Andreoni, Massimo] Univ Hosp Tor Vergata, Clin Infect Dis, Rome, Italy, [Latini, Alessandra] San Gallicano Dermatol Inst, HIV AIDS Unit, Rome, Italy, [Mussini, Cristina] Azienda Osped Univ Policlin, Clin Infect Dis, Modena, Italy, [Aghokeng, Avelin] Virol Lab CREMER IMPM, Yaounde, Cameroon, [Sonnerborg, Anders] Karolinska Inst, Div Clin Microbiol, Stockholm, Sweden, [Neogi, Ujjwal] Karolinska Inst, Div Clin Microbiol, Stockholm, Sweden, [Sonnerborg, Anders] Karolinska Inst, Infect Dis Unit, Stockholm, Sweden, [Neogi, Ujjwal] Karolinska Inst, Infect Dis Unit, Stockholm, Sweden, [Sonnerborg, Anders] Karolinska Univ Hosp, Stockholm, Sweden, [Neogi, Ujjwal] Karolinska Univ Hosp, Stockholm, Sweden, [Fessel, William J.] Kaiser Permanente Med Care Program Northern Calif, San Francisco, CA USA, [Agolory, Simon] Ctr Dis Control & Prevent, Div Global HIV AIDS, Ctr Global Hlth, Atlanta, GA USA, [Raizes, Elliot] Ctr Dis Control & Prevent, Div Global HIV AIDS, Ctr Global Hlth, Atlanta, GA USA, [Yang, Chunfu] Ctr Dis Control & Prevent, Int Lab Branch, Div Global HIV AIDS, Ctr Global Hlth, Atlanta, GA USA, [Blanco, Jose L.] Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Clin Univ, Barcelona, Spain, [Juma, James M.] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania, [Smit, Erasmus] Publ Hlth England, Publ Hlth Lab, Birmingham, W Midlands, England, [Schmidt, Daniel] Robert Koch Inst, Dept Infect Dis Epidemiol HIV AIDS STI & Blood Bo, Berlin, Germany, [Watera, Christine] Uganda Res Unit AIDS, Entebbe, Uganda, [Asio, Juliet] Uganda Res Unit AIDS, Entebbe, Uganda, [Kaleebu, Pontiano] Uganda Res Unit AIDS, Entebbe, Uganda, [Tostevin, Anna] Minist Hlth, Kampala, Uganda, [Tostevin, Anna] UCL, MRC Clin Trials Unit, London, England, [Dunn, David] UCL, MRC Clin Trials Unit, London, England, [El-Hay, Tal] IBM Haifa Res Lab, Haifa, Israel, [Clumeck, Nathan] Univ Libre Bruxelles, St Pierre Univ Hosp, Brussels, Belgium, [Goedhals, Dominique] Univ Orange Free State, Dept Med Microbiol & Virol, Natl Hlth Lab Serv, Bloemfontein, South Africa, [van Vuuren, Cloete] Univ Orange Free State, Dept Med Microbiol & Virol, Natl Hlth Lab Serv, Bloemfontein, South Africa, [Sabin, Caroline] UCL, Infect & Populat Hlth, London, England, [Mukui, Irene] Minist Hlth, Natl AIDS & STI Control Programme, Nairobi, Kenya, [Perno, Carlo F.] INMI L Spallanzani, Antiretroviral Drugs Monitoring Unit, Rome, Italy, [Hunt, Gillian] Natl Inst Communicable Dis, Johannesburg, South Africa, [Morris, Lynn] Natl Inst Communicable Dis, Johannesburg, South Africa, [de Oliveira, Tulio] Wellcome Trust Africa Ctr Hlth & Populat Studies, Durban, South Africa, [Pillay, Deenan] Wellcome Trust Africa Ctr Hlth & Populat Studies, Durban, South Africa, [de Oliveira, Tulio] Univ KwaZulu Natal, Coll Hlth Sci, Durban, South Africa, [Schulter, Eugene] Univ Cologne, Inst Virol, D-50931 Cologne, Germany, [Murakami-Ogasawara, Akio] Natl Inst Resp Dis, Ctr Res Infect Dis, Mexico City, DF, Mexico, [Sirivichayakul, Sunee] Chulalongkorn Univ, Dept Med, Bangkok, Thailand, [Ruxrungtham, Kiat] Chulalongkorn Univ, Dept Med, Bangkok, Thailand, [Mekprasan, Suwanna] Chulalongkorn Univ, Dept Med, Bangkok, Thailand, [Kaleebu, Pontiano] MRC UVRI Uganda Res Unit AIDS, Entebbe, Uganda, Wellcome Trust, MRC, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, and Medical Research Council
Subjects: Cyclopropanes, Anti-HIV Agents, K65r, Drug Resistance, Antiretroviral Therapy, HIV Infections, Global Health, Settore MED/07, Virological failure, Tenofovir disoproxil fumarate, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral, Humans, Emtricitabine, Transmission, Highly Active, Viral, Tenofovir, Africa South of the Sahara, Benzoxazines, HIV-1, Lamivudine, Pre-Exposure Prophylaxis, Retrospective Studies, Reverse Transcriptase Inhibitors, Viral Load, Hiv-1-infected patients, virus diseases, Articles, Antiretroviral therapy, Naive patients, Alkynes, Efavirenz
Abstract: Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count
Published: 2016

40. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author: Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark 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Subjects: 0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund
Published: 2016
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41. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author: Meeks, H.D., Song, H.L., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B.J., Buys, S.S., Hopper, J.L., Southey, M.C., Tesoriero, A., James, P.A., Bruinsma, F., Campbell, I.G., Broeks, A., Schmidt, M.K., Hogervorst, F.B.L., Beckman, M.W., Fasching, P.A., Fletcher, O., Johnson, N., Sawyer, E.J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K.L., Poole, E.M., Tworoger, S.S., Dorfling, C.M., Rensburg, E.J. van, Godwin, A.K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Isaacs, C., Maugard, C., Bojesen, S.E., Flyger, H., Gerdes, A.M., Hansen, T.V.O., Jensen, A., Kjaer, S.K., Hogdall, C., Hogdall, E., Pedersen, I.S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., Hoya, M. de la, Segura, P.P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E.M., Neuhausen, S.L., Ding, Y.C., Castillo, D., Weitzel, J.N., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Karlan, B.Y., Lester, J., Wu, A., Gayther, S., Ramus, S.J., Sieh, W., Whittermore, A.S., Monteiro, A.N.A., Phelan, C.M., Terry, M.B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K.B., Cannioto, R., Olson, S.H., Daly, M.B., Nathanson, K.L., Domchek, S.M., Lu, K.H., Liang, D., Hildebrant, M.A.T., Ness, R., Modugno, F., Pearce, L., Goodman, M.T., Thompson, P.J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruning, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L.M., Aittomaki, K., Butzow, R., Bogdanova, N.V., Dork, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V.M., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K.B.M., Maerken, T. van, Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M.R., Collavoli, A., Hallberg, E., Olson, J.E., Goode, E.L., Hart, S.N., Shimelis, H., Cunningham, J.M., Giles, G.G., Milne, R.L., Healey, S., Tucker, K., Haiman, C.A., Henderson, B.E., Goldberg, M.S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D.M., N. le, Borresen-Dale, A.L., Kristensen, V., Salvesen, H.B., Bjorge, L., Bandera, E.V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R.A.E.M., Ouweland, A.M.W. van der, Andrulis, I.L., Knight, J.A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M.H., Mai, P.L., Loud, J.T., Garcia-Closas, M., Schoemaker, M.J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S.K., Teo, S.H., Yoon, S.Y., Matsuo, K., Hosono, S., Woo, Y.L., Gao, Y.T., Foretova, L., Singer, C.F., Rappaport-Feurhauser, C., Friedman, E., Laitman, Y., Rennert, G., Imyanitov, E.N., Hulick, P.J., Olopade, O.I., Senter, L., Olah, E., Doherty, J.A., Schildkraut, J., Koppert, L.B., Kiemeney, L.A., Massuger, L.F.A.G., Cook, L.S., Pejovic, T., Li, J.M., Borg, A., Ofverholm, A., Rossing, M.A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S.S., Pasini, B.J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B.A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A.C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A.M., Pharoah, P.D.P., Hall, P., Easton, D.F., Couch, F.J., Spurdle, A.B., Goldgar, D.E., EMBRACE, kConFab Investigators, Australia Ovarian Canc Study Grp, HEBON, GEMO Study Collaborators, OCGN, PRostate Canc Assoc Grp, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Obstetrics & Gynecology, Surgery, and [ 1 ] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT USA [ 2 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet 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Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA [ 100 ] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA [ 101 ] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA [ 102 ] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 103 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA [ 104 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA [ 105 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 106 ] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany [ 107 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 108 ] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-80290 Munich, Germany [ 109 ] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany [ 110 ] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany [ 111 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 112 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Cologne, Germany [ 113 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 114 ] Univ Tubingen, Tubingen, Germany [ 115 ] Ruhr Univ Bochum IPA, German Social Accid Insurance & Inst, Inst Prevent & Occupat Med, Bochum, Germany [ 116 ] Univ Helsinki, Dept Oncol, Helsinki, Finland [ 117 ] Helsinki Univ Hosp, Helsinki, Finland [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 119 ] Univ Helsinki, Dept Clin Genet, Helsinki, Finland [ 120 ] Univ Helsinki, Dept Pathol, Helsinki, Finland [ 121 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 122 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 123 ] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden [ 124 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 125 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland [ 126 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 127 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 128 ] VIB, VRC, Leuven, Belgium [ 129 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 130 ] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 131 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 132 ] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany [ 133 ] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany [ 134 ] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany [ 135 ] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany [ 136 ] Charite, Campus Virchov Klinikum, Inst Human Genet, Berlin, Germany [ 137 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 138 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy [ 139 ] Aviano Natl Canc Inst, CRO, Div Expt Oncol, Aviano, Italy [ 140 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 141 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy [ 142 ] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy [ 143 ] ULSS5 Ovest Vicentino, UOC Oncol, Veneto, Italy [ 144 ] Portugese Oncol Inst, Dept Genet, Oporto, Portugal [ 145 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 146 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 147 ] Univ Hosp Pisa, Pisa, Italy [ 148 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 149 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 150 ] Prince Wales Hosp, Sydney, NSW, Australia [ 151 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 152 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 153 ] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada [ 154 ] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada [ 155 ] Univ Cambridge, Sch Med, Cambridge, England [ 156 ] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada [ 157 ] Univ Laval, Quebec City, PQ, Canada [ 158 ] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England [ 159 ] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada [ 160 ] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 161 ] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway [ 162 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 163 ] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway [ 164 ] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway [ 165 ] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA [ 166 ] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA [ 167 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Div Epidemiol,Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA [ 168 ] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 169 ] Univ Oulu, Bioctr Oulu, Oulu, Finland [ 170 ] Northern Finland Lab Ctr Nordlab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 171 ] Erasmus Univ, Med Ctr, Dept Surg Oncol, Rotterdam, Netherlands [ 172 ] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands [ 173 ] Mt Sinai Hosp, Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada [ 174 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 175 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 176 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 177 ] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada [ 178 ] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands [ 179 ] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands [ 180 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 181 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA [ 182 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 183 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 184 ] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland [ 185 ] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland [ 186 ] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland [ 187 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 188 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 189 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 190 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 191 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 192 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia [ 193 ] Univ Malaya, Med Ctr, Fac Med, Canc Res Inst, Kuala Lumpur, Malaysia [ 194 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 195 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan [ 196 ] Univ Malaya, Med Ctr, Dept Obstet & Gynecol, Kuala Lumpur, Malaysia [ 197 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 198 ] Masaryk Mem Canc Inst & Med Fac, Brno, Czech Republic [ 199 ] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria [ 200 ] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria [ 201 ] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel [ 202 ] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 203 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 204 ] B Rappaport Fac Med, Haifa, Israel [ 205 ] NN Petrov Inst Oncol, St Petersburg, Russia [ 206 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 207 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 208 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 209 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 210 ] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03755 USA [ 211 ] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA [ 212 ] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA [ 213 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands [ 214 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands [ 215 ] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA [ 216 ] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA [ 217 ] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA [ 218 ] Lund Univ, Dept Oncol, Lund, Sweden [ 219 ] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden [ 220 ] Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA [ 221 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 222 ] Univ Lund Hosp, Ctr Oncol, Reg Tumour Registry, S-22185 Lund, Sweden [ 223 ] Univ Sheffield, Sheffield Canc Res Dept Oncol, Sheffield, S Yorkshire, England [ 224 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 225 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia [ 226 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 227 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 228 ] Univ Iceland, Sch Med, Reykjavik, Iceland [ 229 ] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland [ 230 ] Inst Oncol, Warsaw, Poland [ 231 ] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Nucl & Radiol Sci & Technol, Energy & Safety, Athens, Greece [ 232 ] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, endocrine system diseases, LOCI, Estrogen receptor, FAMILY-HISTORY, Prostate cancer, 0302 clinical medicine, Ovarian Neoplasms/pathology, Prostate, Risk Factors, Brjóstakrabbamein, Odds Ratio, skin and connective tissue diseases, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Prostatic Neoplasms/genetics, Research Support, Non-U.S. Gov't, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, BRCA2 Protein/genetics, PANCREATIC-CANCER, 3. Good health, SUSCEPTIBILITY GENE, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Codon, Terminator, Female, Risk Factors Substances, Adult, medicine.medical_specialty, Heterozygote, Breast Neoplasms, Blöðruhálskirtilskrabbamein, Breast Neoplasms/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Ovarian Neoplasms/genetics, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Internal medicine, Pancreatic cancer, Krabbameinsrannsóknir, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Lysine/genetics, Krabbamein, Aged, Gynecology, BRCA2 Protein, Proportional hazards model, Lysine, DNA RECOMBINATION, CONSORTIUM, GERM-LINE MUTATION, Prostatic Neoplasms, Odds ratio, Arfgengi, medicine.disease, ESTROGEN-RECEPTOR, 030104 developmental biology, Logistic Models, PTT12, Eggjastokkar, FANCONI-ANEMIA, Ovarian cancer
Abstract: Contains fulltext : 172007.pdf (Publisher’s version ) (Closed access) BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
Published: 2016
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42. Understanding the Functional Plasticity in Neural Networks of the Basal Ganglia in Cocaine Use Disorder: A Role for Allosteric Receptor-Receptor Interactions in A2A-D2 Heteroreceptor Complexes

Author: Borroto-Escuela, Dasiel O., Wydra, Karolina, Pintsuk, Julia, Narvaez, Manuel, Corrales, Fidel, Zaniewska, Magdalena, Agnati, Luigi F., Franco, Rafael, Tanganelli, Sergio, Ferraro, Luca, Filip, Malgorzata, Fuxe, Kjell, [Borroto-Escuela, Dasiel O.] Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden, [Pintsuk, Julia] Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden, [Agnati, Luigi F.] Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden, [Fuxe, Kjell] Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden, [Borroto-Escuela, Dasiel O.] Univ Urbino, Physiol Sect, Dept Biomol Sci, Campus Sci Enrico Mattei,Via Cale Suore 2, I-61029 Urbino, Italy, [Borroto-Escuela, Dasiel O.] Observ Cubanos Neurociencias, Grp Bohio Estudio, Yaguajay, Cuba, [Corrales, Fidel] Observ Cubanos Neurociencias, Grp Bohio Estudio, Yaguajay, Cuba, [Wydra, Karolina] Polish Acad Sci, Inst Pharmacol, Lab Drug Addict Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland, [Zaniewska, Magdalena] Polish Acad Sci, Inst Pharmacol, Lab Drug Addict Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland, [Filip, Malgorzata] Polish Acad Sci, Inst Pharmacol, Lab Drug Addict Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland, [Pintsuk, Julia] Univ Tartu, Inst Biomed & Translat Med, Dept Physiol, 19 Ravila St, EE-50411 Tartu, Estonia, [Narvaez, Manuel] Univ Malaga, Inst Invest Biomed Malaga, Fac Med, Malaga, Spain, [Corrales, Fidel] Univ Malaga, Inst Invest Biomed Malaga, Fac Med, Malaga, Spain, [Corrales, Fidel] Ctr Nacl Neurociencias, Havana, Cuba, [Franco, Rafael] Univ Barcelona, Fac Biol, Dept Bioquim & Biomed Mol, Barcelona, Spain, [Franco, Rafael] Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Madrid, Spain, [Tanganelli, Sergio] Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy, [Ferraro, Luca] Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy, [Tanganelli, Sergio] Univ Ferrara, Dept Med Sci, Ferrara, Italy, Swedish Medical Research Council, AFA Forsakring, Hjarnfonden, and Institute of Pharmacology Polish Academy of Sciences (Krakow, Poland)
Subjects: D2 receptors, Modulation, Article Subject, Synaptic-transmission, Adenosine a(2a) receptors, Dopamine, Communication, Integrative mechanism, Glutamate, Proximity ligation assay, Higher-order oligomers
Abstract: Our hypothesis is that allosteric receptor-receptor interactions in homo- and heteroreceptor complexes may form the molecular basis of learning and memory. This principle is illustrated by showing how cocaine abuse can alter the adenosine A2AR-dopamine D2R heterocomplexes and their receptor-receptor interactions and hereby induce neural plasticity in the basal ganglia. Studies with A2AR ligands using cocaine self-administration procedures indicate that antagonistic allosteric A2AR-D2R heterocomplexes of the ventral striatopallidal GABA antireward pathway play a significant role in reducing cocaine induced reward, motivation, and cocaine seeking. Anticocaine actions of A2AR agonists can also be produced at A2AR homocomplexes in these antireward neurons, actions in which are independent of D2R signaling. At the A2AR-D2R heterocomplex, they are dependent on the strength of the antagonistic allosteric A2AR-D2R interaction and the number of A2AR-D2R and A2AR-D2R-sigma1R heterocomplexes present in the ventral striatopallidal GABA neurons. It involves a differential cocaine-induced increase in sigma1Rs in the ventral versus the dorsal striatum. In contrast, the allosteric brake on the D2R protomer signaling in the A2AR-D2R heterocomplex of the dorsal striatopallidal GABA neurons is lost upon cocaine self-administration. This is potentially due to differences in composition and allosteric plasticity of these complexes versus those in the ventral striatopallidal neurons.
Published: 2016

43. Caspase-8 inhibition represses initial human monocyte activation in septic shock model

Author: Johanna Rodhe, José Antonio Pérez-Simón, Teresa Caballero-Velázquez, Luis Ignacio Sánchez-Abarca, Antonio J. Herrera, José L. Venero, Alejandro Carrillo-Jimenez, P Vlachos, Maria Jose Oliva-Martin, Bertrand Joseph, Albert García-Quintanilla, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (España), European Commission, Swedish Research Council, Swedish Childhood Cancer Foundation, Swedish Cancer Society, Swedish Parkinson Foundation, Swedish Brain Foundation, [Jose Oliva-Martin, Maria] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Carrillo-Jimenez, Alejandro] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Jose Herrera, Antonio] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Garcia-Quintanilla, Albert] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Luis Venero, Jose] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Jose Oliva-Martin, Maria] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Rodhe, Johanna] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Vlachos, Pinelopi] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Joseph, Bertrand] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Jose Oliva-Martin, Maria] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Sanchez-Abarca, Luis Ignacio] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Caballero-Velazquez, Teresa] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Perez-Simon, Jose Antonio] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, SwedenHosp Univ Virgen del Rocio, Dept Haematol, Malaga, Spain, MINECO/FEDER, UE, Junta of Andalucia, and Swedish Cancer Foundation
Subjects: 0301 basic medicine, Monocyte, Monocytes, caspase-8, sepsis, Mice, Mechanisms, Il-1-beta, Cells, Cultured, Caspase, Mice, Knockout, Caspase 8, biology, Pro-inflammatory activation, Switch, Caspase Inhibitors, Shock, Septic, Cell biology, medicine.anatomical_structure, Oncology, Necroptosis, monocyte, Cytokines, medicine.symptom, Cell activation, Caspase-8, Programmed cell death, Macrophage differentiation, necroptosis, Inflammation, 03 medical and health sciences, Sepsis, Pathology Section, medicine, Animals, Humans, Septic shock, medicine.disease, Research Paper: Pathology, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, inflammation, Immunology, biology.protein, Surviving sepsis, Cell-death
Abstract: In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1β and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source., This work was supported by grants SAF2012-39029 and SAF2015-64171R (MINECO/FEDER, UE), the Junta of Andalucía (P10-CTS-6494), the Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Foundation, Swedish Parkinson Foundation and the Swedish Brain Foundation.
Published: 2016

44. Off-label use of rituximab for systemic lupus erythematosus in Europe

Author: Ryden-Aulin, Monica, Boumpas, Dimitrios, Bultink, Irene, Rubio, Jose Luis Callejas, Caminal-Montero, Luis, Castro, Antoni, Colodro Ruiz, Agustin, Doria, Andrea, Domer, Thomas, Gonzalez-Echavarri, Cristina, Gremese, Elisa, Houssiau, Frederic A., Huizinga, Tom, Inana, Murat, Isenberg, David, Luliano, Annamaria, Jacobsen, Soren, Jimenez-Alonso, Juan, Kovacs, Laszlo, Mariette, Xavier, Mosca, Marta, Nived, Ola, Oristrell, Joaquim, Ramos-Casals, Manuel, Rascon, Javier, Ruiz-Irastorza, Guillermo, Saez-Comet, Luis, Salvador Cervello, Gonzalo, Cervello, Gonzalo Salvador, Sebastiani, Gian Domenico, Squatrito, Danilo, Szucs, Gabriella, Voskuyl, Alexandre, van Vollenhoven, Ronald, Rheumatology, AII - Inflammatory diseases, [Ryden-Aulin, Monica] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Unit Clin Therapy Res, Stockholm, Sweden, [van Vollenhoven, Ronald] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Unit Clin Therapy Res, Stockholm, Sweden, [Boumpas, Dimitrios] Natl & Kapodestrian Univ Athens, Attikon Univ Hosp, Joint Acad Rheumatol Program, Med Sch, Athens, Greece, [Boumpas, Dimitrios] Natl & Kapodestrian Univ Athens, Attikon Univ Hosp, Dept Med 4, Med Sch, Athens, Greece, [Bultink, Irene] Amsterdam Rheumatol & Immunol Ctr, Tepartment Rheumatol, Amsterdam, Netherlands, [Rubio, Jose Luis Callejas] Hosp San Cecilio, Unit Autoimmune Dis, Granada, Spain, [Caminal-Montero, Luis] Hosp Univ Cent Asturias, Internal Med Dept, Autoimmune System Dis Unit, Oviedo, Spain, [Castro, Antoni] Rovira & Virgili Univ URV, Univ Hosp Sant Joan Reus, lnternal Med Dept Univ, IISPV, Reus, Spain, [Colodro Ruiz, Agustin] Pasaje Nueva Victoria,2,2do C, Jaen, Spain, [Doria, Andrea] Univ Padua, Dept Med, Rheumatol Unit, Padua, Italy, [Domer, Thomas] Charite Univ Med Berlin, Dept Med Rheumatol & Clin Immunol, Berlin, Germany, [Gonzalez-Echavarri, Cristina] Univ Basque Country, Cruces Univ Hosp, BioCruces Hlth Res Inst, Autoimmune Dis Res Unit,Dept Internal Med, Baracaldo, Spain, [Ruiz-Irastorza, Guillermo] Univ Basque Country, Cruces Univ Hosp, BioCruces Hlth Res Inst, Autoimmune Dis Res Unit,Dept Internal Med, Baracaldo, Spain, [Gremese, Elisa] Univ Cattolica Sacro Cuore, Inst Rheumatol & Affine Sci IRSA, Rome, Italy, [Houssiau, Frederic A.] Catholic Univ Louvain, Pole Pathol Rhumatismales Inflammatoires & Syst, Clin Univ St Luc, Serv Rhumatol, Brussels, Belgium, [Huizinga, Tom] Leiden Univ, Med Ctr, Dept Rheumatol, C1-41, Leiden, Netherlands, [Inana, Murat] Istanbul Univ, Istanbul Fac Med, Dept Internal Med, Div Rheumatol, Istanbul, Turkey, [Isenberg, David] UCL, Rayne Bldg, London, England, [Luliano, Annamaria] San Camillo Hosp, Rheumatol Unit, Rome, Italy, [Jacobsen, Soren] Univ Copenhagen, Rigshosp, Ctr Rheumatol & Spine Dis, Copenhagen Lupus & Vasculitis Clin, Copenhagen, Denmark, [Jimenez-Alonso, Juan] Univ Virgen Nieves Hosp, lnternal Dept, Granada, Spain, [Kovacs, Laszlo] Univ Szeged, Albert Szent Gyorgyi Hlth Ctr, Fac Med, Dept Rheumatol, Szeged, Hungary, [Mariette, Xavier] Univ Paris Sud, Hopitaux Univ Paris Sud, Rhumatol Responsable Unite Rech Clin, INSERM U1184, Paris, France, [Mosca, Marta] Rheumatol Unit, Pisa, Italy, [Nived, Ola] Skane Univ Hosp, Rheumatol Clin, Lund, Sweden, [Oristrell, Joaquim] Univ Autonoma Barcelona, Hosp Sabadell, Internal Med Dept, Catalunya, Spain, [Ramos-Casals, Manuel] CELLEX IDIBAPS, Josep Font Autoimmune Lab, ICMiD, Dept Autoimmune Dis, Barcelona, Spain, [Rascon, Javier] Carrer Sabateres, 9-1,Alare, Islas Baleares, Spain, [Saez-Comet, Luis] Hosp Univ Miguel Servet Zaragoza, Unidad Enfermedades Autoinmunes Sistem, Paseo Isabel Catolica, Zaragoza, Spain, [Salvador Cervello, Gonzalo] Hosp Univ & Politecn La Fe, Inmunopathol & Autoimmune Area, Dept Internal Med, Valencia, Spain, [Sebastiani, Gian Domenico] Osped San Camillo, UOC Reumatol, Circonvallaz Gianicolense 87, Rome, Italy, [Squatrito, Danilo] Univ Florence, Dept Sperimental & Clin Med, Florence, Italy, [Szucs, Gabriella] Univ Debrecen, Inst Med, Dept Rheumatol, Debrecen, Hungary, [Voskuyl, Alexandre] Vrije Univ Amsterdam, Med Ctr, Amsterdam Rheumatol & Immunol Ctr ARC, Amsterdam, Netherlands, [van Vollenhoven, Ronald] Karolinska Univ Hosp Stockholm, Rheumatol Clin, Stockholm, Sweden, [van Vollenhoven, Ronald] Amsterdam Rheumatol & Immunol Ctr ARC, AMC Mail F4-105, Amsterdam, Netherlands, MSD, Lilly Netherlands, Roche, UCB, Sanofi, and RvV
Subjects: medicine.medical_specialty, Disease duration, Immunology, Lupus nephritis, DMARDs (biologic), Klinikai orvostudományok, Off-label use, Systemic Lupus Erythematosus, Article, Disease activity, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, Lupus Nephritis, Medicine (all), In patient, 030212 general & internal medicine, skin and connective tissue diseases, 030203 arthritis & rheumatology, business.industry, Orvostudományok, General Medicine, medicine.disease, Disease control, 3. Good health, Rituximab, business, medicine.drug
Abstract: OBJECTIVES: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy.METHODS: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries.RESULTS: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy.CONCLUSIONS: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.
Published: 2016
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45. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Laura J. Scott, Neil Robertson, Anders Hamsten, Domenico Palli, Susanne Moebus, Bernhard O. Boehm, Gunnar Sigurðsson, Paul W. Franks, C. N. A. Palmer, Sonali Pechlivanis, Katharine R. Owen, Michael E. Reschen, Sarah Edkins, Jason Carey, Christopher A. O’Callaghan, Norman Klopp, Caroline S. Fox, Petter Storm, N. William Rayner, Johan G. Eriksson, Thomas Illig, Anubha Mahajan, Erik Ingelsson, Allan Linneberg, Andrew R. Wood, Oddgeir L. Holmen, Nicola L. Beer, Mark I. McCarthy, Frank B. Hu, Peter Almgren, Heiner Boeing, Peter Donnelly, Carl Platou, Veikko Salomaa, Karl-Heinz Jöcke, Wen-Hong L. Kao, Lori L. Bonnycastle, Denis Rybin, Benjamin F. Voight, Peter Kraft, Inês Barroso, Claudia Langenberg, Teresa Ferreira, Peter Kovacs, Anne Raimondo, Christian Theil Have, Ulf de Faire, Torben Hansen, Han Chen, James B. Meigs, Timothy M. Frayling, Noël P. Burtt, Gerald Steinbach, Eric Boerwinkle, Michael Stumvoll, Stefan Gustafsson, Lars Lind, Andrew D. Morris, Alena Stančáková, Panagiotis Deloukas, Kari Stefansson, Augustine Kong, Hans A. Kestler, Andrew T. Hattersley, Beverley Balkau, Lorenzo Pasquali, Yingchang Lu, Nicola D. Kerrison, George B. Grant, Eeva Korpi-Hyövälti, Steven Wiltshire, Karl Gertow, Jorge Ferrer, Barbara Thorand, Inga Prokopenko, Matthias Blüher, Yvonne T. van der Schouw, Olga McLeod, Oluf Pedersen, Leena Peltonen, Anil Chalisey, Eleftheria Zeggini, Joseph Trakalo, Eric J.G. Sijbrands, Rainer Rauramaa, Guillaume Charpentier, Satu Männistö, Cordelia Langford, Lewin Eisele, Damiano Baldassarre, Lennart C. Karssen, Rona J. Strawbridge, Ghazala Mirza, Peter S. Chines, Roman Wennauer, Sara M. Willems, Erwin P. Bottinger, Timo Saaristo, Stéphane Cauchi, Ching-Ti Liu, Martijn van de Bunt, Valgerdur Steinthorsdottir, David Altshuler, Hyun Min Kang, Michael Boehnke, Jaakko Tuomilehto, Peter M. Nilsson, Kyle J. Gaulton, Jian'an Luan, Loic Yengo, David Couper, Reedik Mägi, Harald Grallert, Simone Wahl, Juha Saltevo, Phoenix Kwan, Cecilia M. Lindgren, Peter Lichtner, Richard N. Bergman, Andrew Crenshaw, João Fadista, Michael Roden, Annette Peters, Robert A. Scott, Unnur Thorsteinsdottir, James S. Pankow, Yeji Lee, Cornelia M. van Duijn, Samuli Ripatti, Francis S. Collins, Stéphane Lobbens, Niels Grarup, Ruth J. F. Loos, Julia Meyer, Marit E. Jørgensen, Christian Herder, Inger Njølstad, John R. B. Perry, Markus M. Nöthen, Man Li, Martina Müller-Nurasyid, Valeriya Lyssenko, Pierre Fontanillas, Michael D. Linderman, Leena Kinnunen, Jana K. Rundle, Elena Tremoli, Marilyn C. Cornelis, Tanya M. Teslovich, Todd Green, Raimund Erbel, Elisabeth M. van Leeuwen, Bengt Sennblad, Olle Melander, Sirkka Keinänen-Kiukaanniemi, Markku Laakso, Eero Lindholm, Alex S. F. Doney, Anke Tönjes, Maija Hassinen, Thomas W. Mühleisen, Gonçalo R. Abecasis, Nancy L. Pedersen, Thomas Sparsø, Johanna Kuusisto, Dorothée Thuillier, Qi Sun, Ian Dunham, Himanshu Chheda, Adam E. Locke, Philippe Froguel, Nicholas J. Wareham, Bruna Gigante, Jose C. Florez, Mozhgan Dorkhan, Omri Gottesman, Liming Liang, Anna Jonsson, Tiinamaija Tuomi, Leif Groop, Steve E. Humphries, Heikki A. Koistinen, Kristian Hveem, Astradur B. Hreidarsson, Jason Flannick, Torben Jørgensen, Clement Ma, Mattias Frånberg, Ewan Birney, Andrew P. Morris, Timo A. Lakka, Rob M. van Dam, Heather M. Stringham, Christian Gieger, Elodie Eury, Konstantin Strauch, Anna L. Gloyn, Rafn Benediktsson, Andres Metspalu, David J. Hunter, Karen L. Mohlke, Gudmar Thorleifsson, Josée Dupuis, Emmi Tikkanen, Christian Fuchsberger, Evelin Mihailov, Christopher J. Groves, Soren K. Thomsen, Tõnu Esko, Anne U. Jackson, Karin Leander, Douglas M. Ruderfer, Nikolay Oskolkov, Sekar Kathiresan, Robert Sladek, Lu Qi, Jasmina Kravic, Carmen Navarro, Epidemiology, Dermatology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Stanford Univ, Dept Genet, Stanford, CA 94305 USA [ 3 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 4 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 5 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 6 ] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England [ 7 ] Wellcome Trust Sanger Inst, Hinxton, England [ 8 ] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England [ 9 ] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England [ 10 ] Broad Inst Harvard & MIT, Cambridge, MA USA [ 11 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark [ 12 ] European Genom Inst Diabet, Lille Inst Biol, Lille, France [ 13 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 14 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany [ 15 ] German Ctr Diabet Res, Neuherberg, Germany [ 16 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 17 ] Sci Life Lab, Stockholm, Sweden [ 18 ] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden [ 19 ] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany [ 20 ] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany [ 21 ] Finnish Inst Mol Med, Helsinki, Finland [ 22 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 23 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 24 ] deCODE Genet Amgen Inc, 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Diabet, Malmo, Sweden [ 38 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 39 ] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy [ 40 ] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France [ 41 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 42 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 43 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 44 ] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany [ 45 ] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany [ 46 ] German Inst Human Nutr, Potsdam, Germany [ 47 ] NHGRI, US NIH, Bethesda, MD 20892 USA [ 48 ] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA [ 49 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 50 ] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA [ 51 ] Univ N Carolina, Dept Biostat, Collaborat Studies 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Boston, MA 02115 USA [ 66 ] Harvard Univ, Sch Med, Boston, MA USA [ 67 ] Lund Univ, Dept Clin Sci, Malmo, Sweden [ 68 ] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden [ 69 ] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 70 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 71 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 72 ] Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany [ 73 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway [ 74 ] UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England [ 75 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 76 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 77 ] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark [ 78 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 79 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 80 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 81 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany [ 82 ] Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark [ 83 ] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark [ 84 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany [ 85 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England [ 86 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 87 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 88 ] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany [ 89 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 90 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany [ 91 ] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany [ 92 ] Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain [ 93 ] CIBERESP, Madrid, Spain [ 94 ] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain [ 95 ] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England [ 96 ] Canc Res & Prevent Inst ISPO, Florence, Italy [ 97 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 98 ] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 99 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA [ 100 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 101 ] Univ Med Ctr Utrecht, Utrecht, Netherlands [ 102 ] Iceland Heart Assoc, Kopavogur, Iceland [ 103 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 104 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 105 ] Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany [ 106 ] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland [ 107 ] Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland [ 108 ] Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland [ 109 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 110 ] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England [ 111 ] European Mol Biol Lab, EBI, Hinxton, England [ 112 ] Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain [ 113 ] Josep Carreras Leukaemia Res Inst, Badalona, Spain [ 114 ] CIBERDEM, Barcelona, Spain [ 115 ] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England [ 116 ] Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain [ 117 ] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA [ 118 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 119 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 120 ] Massachusetts Gen Hosp, Diabet 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Boston, MA USA [ 164 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 165 ] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: endocrine system diseases, Medizin, Genome-wide association study, Glucose homeostasis, WIDE ASSOCIATION, Association mapping, Non-U.S. Gov't, Genome-Wide Association Study, Regulation of gene expression, Genetics, Genetics & Heredity, LARGE-SCALE ASSOCIATION, Research Support, Non-U.S. Gov't, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Genomics, 3. Good health, TRANSCRIPTION FACTORS, Liver, Hepatocyte Nuclear Factor 3-beta, Medical Genetics, Life Sciences & Biomedicine, Chromatin Immunoprecipitation, endocrine system, European Continental Ancestry Group/genetics, Biology, GENOTYPE IMPUTATION, Research Support, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, N.I.H, Sykursýki, Islets of Langerhans, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, HUMAN PANCREATIC-ISLETS, GLYCEMIC TRAITS, Journal Article, SNP, Humans, Genetic Predisposition to Disease, Comparative Study, Enhancer, Medicinsk genetik, Science & Technology, Binding Sites, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Receptor, Melatonin, MT2, Extramural, Molecular Sequence Annotation, Arfgengi, 06 Biological Sciences, Genetic Predisposition to Disease/genetics, BETA-CELL, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Case-Control Studies, Gene-Environment Interaction, GLUCOSE-HOMEOSTASIS, Chromatin immunoprecipitation, Developmental Biology
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381
Published: 2015
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46. Polygenic risk scores for schizophrenia and bipolar disorder predict creativity

Author: Agnar Helgason, Robert Power, Fredrik Ullén, Patrik K. E. Magnusson, Augustine Kong, Frank J. A. van Rooij, Henning Tiemeier, Dorret I. Boomsma, Thorgeir E. Thorgeirsson, Gyda Bjornsdottir, Michel M Nivard, Jouke J. Hottenga, Lambertus A. Kiemeney, Abdel Abdellaoui, David Cesarini, Magnus Johannesson, Engilbert Sigurdsson, Philipp Koellinger, Cornelius A. Rietveld, Andres Ingason, Stacy Steinberg, G. Bragi Walters, Daniel F. Gudbjartsson, Gonneke Willemsen, Hreinn Stefansson, Tessel E. Galesloot, Kari Stefansson, Albert Hofman, Daniel J. Benjamin, [ 1 ] deCODE Genet Amgen, Reykjavik, Iceland [ 2 ] Kings Coll London, Inst Psychiat, Genet & Dev Psychiat Ctr, MRC Social, London WC2R 2LS, England [ 3 ] Erasmus Univ, Erasmus Sch Econ, Rotterdam, Netherlands [ 4 ] Vrije Univ Amsterdam, Dept Biol Psychol, Netherlands Twin Register, Amsterdam, Netherlands [ 5 ] Stockholm Sch Econ, Dept Econ, Stockholm, Sweden [ 6 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands [ 7 ] Ctr Expt Social Sci, New York, NY USA [ 8 ] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA USA [ 9 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 10 ] Karolinska Inst, Dept Neurosci, Stockholm, Sweden [ 11 ] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands [ 12 ] Landspitali Univ Hosp, Dept Psychiat, Reykjavik, Iceland [ 13 ] Univ Iceland, Dept Anthropol, Reykjavik, Iceland [ 14 ] Univ Amsterdam, Fac Econ & Business, Amsterdam, Netherlands, Applied Economics, Epidemiology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Complex Trait Genetics
Subjects: Netherlands Twin Register (NTR), Sköpunargáfa, medicine.medical_specialty, Psychosis, Multifactorial Inheritance, Bipolar Disorder, media_common.quotation_subject, Genome-wide association study, Creativity, 03 medical and health sciences, 0302 clinical medicine, Geðklofi, mental disorders, medicine, Bipolar disorder, Psychiatry, media_common, Geðhvarfasýki, Extramural, General Neuroscience, Arfgengi, medicine.disease, 3. Good health, 030227 psychiatry, Schizophrenia, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Polygenic risk score, Psychology, 030217 neurology & neurosurgery, Clinical psychology, Cohort study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10(-6) and 3.8 × 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots. Innovative Medicines Initiative 115008 European Union GA 286213 National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust King's College London Netherlands Organisation for Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 RIDE2 Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture, and Science Ministry for Health, Welfare, and Sports European Commission (DG XII) Municipality of Rotterdam Netherlands Organization for Scientific Research (NWO) MagW/ZonMW BBMRI-NL 184.021.007 VU University Institute for Health and Care Research (EMGO+) Neuroscience Campus Amsterdam European Science Council (ERC) Genetics of Mental Illness 230374 Avera Institute for Human Genetics and US National Institute of Mental Health 1RC2MH089951-01 1RC2 MH089995 Ragnar Soderberg Foundation E9/11 Swedish Research Council 421-2013-1061 Jan Wallander and Tom Hedelius Foundation P2012-0002:1 Sven and Dagmar Salen Foundation Bank of Sweden Tercentenary Foundation M11-0451:1 Karolinska Institutet Netherlands Scientific Organization NWO 480-05-003 info:eu-repo/grantAgreement/EC/FP7/286213
Published: 2015
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47. Health-related quality of life in food-allergic adults from eight European countries

Author: Bertine M. J. Flokstra-de Blok, Peter Burney, Marek L. Kowalski, E. J. Duiverman, Monteserrat Fernandéz-Rivas, Paweł Starosta, Ewa Rokicka, Belén de la Hoz Caballer, Nikos Papadopoulos, Sonia Vásquez-Cortés, Lynn J. Frewer, N. J. Goossens, Monica Jedrzejczak-Czechowicz, Marianne Heibert Arnlind, Anthony E.J. Dubois, L. Barreales, Ricardo Asero, Sven-Arne Jansson, Gerbrich N. van der Meulen, André C. Knulst, Michael Clausen, Ashok Purohit, Imnaculada Cerecedo, Groningen Research Institute for Asthma and COPD (GRIAC), and [ 1 ] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergy, Groningen, Netherlands [ 2 ] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Groningen, Netherlands [ 3 ] Univ Groningen, Univ Med Ctr Groningen, Dept Gen Practice, Groningen, Netherlands [ 4 ] Martini Hosp, Dept Pediat Allergy, Groningen, Netherlands [ 5 ] Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden [ 6 ] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden [ 7 ] Clin San Carlo, Ambulatorio Allergol, Paderno Dugnano, Italy [ 8 ] Hosp Clin San Carlos, IdISSC, Res Unit, Dept Prevent Med, Madrid, Spain [ 9 ] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dept Resp Epidemiol & Publ Hlth, London, England [ 10 ] Hosp Univ Sureste, Secc Alergol, Madrid, Spain [ 11 ] Univ Hosp, Landspitali, Dept Allergy, Reykjavik, Iceland [ 12 ] Hosp Clin San Carlos, IdISSC, Dept Allergy, Madrid, Spain [ 13 ] Food Safety & Consumer Behav, Mkt & Consumer Behaviour Grp, Wageningen, Netherlands [ 14 ] Newcastle Univ, SAFRD, CRE, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England [ 15 ] Hosp Ramon & Cajal, Dept Allergy, E-28034 Madrid, Spain [ 16 ] Med Univ Lodz, Dept Immunol Rheumatol & Allergy, Lodz, Poland [ 17 ] Univ Med Ctr Utrecht, Dept Dermatol Allergol, Utrecht, Netherlands [ 18 ] Univ Athens, Dept Allergy, Pediat Clin 2, Athens, Greece [ 19 ] Univ Strasbourg, Univ Hosp, Dept Chest Dis, Div Allergy, Strasbourg, France [ 20 ] Univ Lodz, Fac Econ & Sociol, PL-90131 Lodz, Poland
Subjects: Pulmonary and Respiratory Medicine, Quality of Life/psychology, Adult, Male, Pediatrics, medicine.medical_specialty, Food Hypersensitivity/pathology, Fæðuofnæmi, Immunology, QUESTIONNAIRE, CHILDREN, Lífsgæði, DISEASE, Quality of life (healthcare), Questionnaires/standards, Cronbach's alpha, Food allergy, Environmental health, Internal consistency, Surveys and Questionnaires, medicine, Immunology and Allergy, Humans, UK, Community survey, VALIDITY, Health related quality of life, business.industry, Food Hypersensitivity/psychology, Construct validity, Independent measure, Middle Aged, medicine.disease, humanities, PREVALENCE, Europe, Quality of Life, Female, business, Fæðuóþol, Food Hypersensitivity/immunology, BURDEN, METHODOLOGY, Food Hypersensitivity, FORM
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page Food allergy can impair health-related quality of life (HRQL). Food Allergy Quality of Life Questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ-AF). HRQL has not, to date, been measured across different European countries using a uniform methodology. To translate and validate the FAQLQ-AF for use in 8 European countries (Iceland, The Netherlands, Poland, France, Spain, Italy, Greece, and Sweden). The English FAQLQ-AF was translated, back-translated, and compared for use in the 8 relevant European languages. Adults with a perceived food allergy were recruited from outpatient departments and through a community survey. Participants completed the FAQLQ-AF, the Food Allergy Independent Measure, and questions concerning participants' characteristics. Validity of the FAQLQ-AF was analyzed for use in the 8 countries. The FAQLQ-AF had strong construct validity (r > 0.59) and an excellent internal consistency (Cronbach α > 0.95) in all countries. Total FAQLQ-AF scores (range 3.2-5.0) were significantly different across participating countries. The FAQLQ-AF is a suitable and valid instrument for measuring HRQL in food-allergic adults in Iceland, The Netherlands, Poland, France, Spain, Italy, Greece, and Sweden. The impact of food allergy on HRQL seems to differ among adults from the 8 participating European countries. Stichting Astmabestrijding 2009/014 Centre for Allergy Research at Karolinska Institutet Swedish Asthma and Allergy Foundation Sahlgrenska University Hospital Sweden info:eu-repo/grantAgreement/EC/FP7/514000
Published: 2014

48. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Author: Carl A. Anderson, Konstantinos N. Lazaridis, Isabelle Cleynen, Wesley K. Thompson, Ole A. Andreassen, Andreas Teufel, Felix Braun, Einar Björnsson, John D. Rioux, Roger W. Chapman, Inke R. König, Javier Gutierrez-Achury, Gabriele Mayr, Stefan Schreiber, Stephan Brand, Mitja Mitrovic, Annika Bergquist, Michael P. Manns, Jean-Paul Achkar, Simon M. Rushbrook, Cyriel Y. Ponsioen, Martina Sterneck, Kirsten Muri Boberg, Christian Rust, Andrew J. Schork, Albert Parés, Gideon M. Hirschfield, Graeme J.M. Alexander, Espen Melum, Bertus Eksteen, Juliane Winkelmann, Cisca Wijmenga, Ingo Thomsen, Hanns-Ulrich Marschall, Isis Ricaño-Ponce, Erik Schrumpf, Peter J. P. Croucher, Jimmy Z. Liu, Richard H. Duerr, Nadezhda Tsankova Doncheva, Annarosa Floreani, Eva Ellinghaus, Markus M. Nöthen, Brian D. Juran, Judy H. Cho, Mario Albrecht, Stefan Herms, Tobias J. Weismüller, Leonid Padyukov, Virpi Leppa, Morten H. Vatn, Mark S. Silverberg, Tobias Müller, Olivier Chazouillères, Domenico Alvaro, Christoph Schramm, Ruslan Dorfman, Richard Sandford, David A. van Heel, Rinse K. Weersma, Suna Onengut-Gumuscu, Anders M. Dale, Martti Färkkilä, Brijesh Srivastava, Severine Vermeire, Trine Folseraas, Vito Annese, Pietro Invernizzi, Tejas Shah, Daniel Gotthardt, Janna Saarela, Christopher L. Bowlus, Sigrid Næss, Andrew Mason, Stephen S. Rich, Johannes R. Hov, Peter R. Durie, Andre Franke, Kristian Hveem, Tom H. Karlsen, Piotr Milkiewicz, Miquel Sans, Georgios N. Dalekos, David Ellinghaus, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Wellcome Trust Sanger Inst, Cambridge, England, Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Norwegian PSC Res Ctr,Dept Transplantat Med, Oslo, Norway Oslo Univ Hosp, Rikshosp, Internal Med Res Inst, KG Jebsen Inflammat Res Ctr, Oslo, Norway Univ Oslo, Inst Clin Med, Oslo, Norway Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Sect Gastroenterol,Dept Transplantat Med, Oslo, Norway Univ Kiel, Inst Clin Mol Biol, Kiel, Germany Dept Gastroenterol & Hepatol, Norfolk, VA USA Univ Hosp Natl Hlth Serv NHS Trust, Norwich, Norfolk, England Max Planck Inst Informat, D-66123 Saarbrucken, Germany Oslo Univ Hosp, Div Mental Hlth & Addict, KG Jebsen Ctr Psychosis Res, Oslo, Norway Univ Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany Hannover Med Sch, Integrated Res & Treatment Ctr Transplantat IFB T, Hannover, Germany Univ Calgary, Dept Med, Snyder Inst Chron Dis, Calgary, AB, Canada Humanitas Clin & Res Ctr, Ctr Autoimmune Liver Dis, Rozzano, Italy Univ Toronto, Dept Med, Div Gastroenterol, Toronto, ON, Canada NIHR, Liver Res Ctr, Biomed Res Unit, Birmingham, W Midlands, England Univ Heidelberg Hosp, Dept Med, Heidelberg, Germany Univ Barcelona, IDIBAPS, CIBERehd, Liver Unit,Hosp Clin, Barcelona, Spain Mayo Clin, Coll Med, Ctr Basic Res Digest Dis, Div Gastroenterol & Hepatol, Rochester, MN USA Pomeranian Med Univ, Liver Unit, Szczecin, Poland Pomeranian Med Univ, Liver Res Labs, Szczecin, Poland Univ Munich, Dept Med 2, Munich, Germany Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany Charite, Dept Internal Med Hepatol & Gastroenterol, D-13353 Berlin, Germany Univ Cambridge, Acad Dept Med Genet, Cambridge, England Univ Thessaly, Sch Med, Dept Med, Larisa, Greece Univ Thessaly, Sch Med, Larisa, Greece Univ Bonn, Inst Human Genet, Bonn, Germany Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany Tech Univ Munich, Dept Neurol, D-80290 Munich, Germany German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany Univ Groningen, Dept Genet, Groningen, Netherlands Univ Med Ctr Schleswig Holstein, Dept Gen Visceral Thorac Transplantat & Pediat Su, Kiel, Germany Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA Univ Med Ctr Hamburg Eppendorf, Dept Hepatobiliary Surg & Transplantat, Hamburg, Germany Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany Univ Alberta, Div Gastroenterol & Hepatol, Edmonton, AB, Canada Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland Univ Helsinki, FIMM, Publ Hlth Genom Unit, Helsinki, Finland Natl Inst Hlth & Welf, Helsinki, Finland Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada Univ Roma La Sapienza, Dept Clin Med, Div Gastroenterol, Rome, Italy Univ Padua, Dept Surg Oncol & Gastroenterol Sci, Padua, Italy Univ Virginia, Div Endocrinol & Metab, Ctr Publ Hlth Genom, Charlottesville, VA USA Univ Virginia, Dept Internal Med, Div Endocrinol & Metab, Charlottesville, VA USA Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA Univ Calif San Diego, Grad Program Cognit Sci, La Jolla, CA 92093 USA Med Univ Lubeck, Inst Med Biometry & Stat, D-23538 Lubeck, Germany Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway Katholieke Univ Leuven, Dept Clin & Expt Med, Louvain, Belgium Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England Landspitali Univ Hosp, Dept Internal Med, Div Gastroenterol & Hepatol, Reykjavik, Iceland Hosp Sick Children, Physiol & Expt Med Res Inst, Toronto, ON M5G 1X8, Canada Akershus Univ Hosp, EpiGen, Nordbyhagen, Norway Mt Sinai Hosp, Inflammatory Bowel Dis IBD Grp, Zane Cohen Ctr Digest Dis, Toronto, ON M5G 1X5, Canada Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden Karolinska Univ Hosp Solna, Stockholm, Sweden Univ Munich, Univ Hosp Munich Grosshadern, Dept Med 2, Munich, Germany Ctr Med Teknon, Dept Digest Dis, Barcelona, Spain Casa Sollievodella Sofferenza Hosp, Ist Ricovero & Cura Carattere Sci, Div Gastroenterol, San Giovanni Rotondo, Italy Azienda Osped Univ Careggi, Unit Gastroenterol SOD2, Florence, Italy Cleveland Clin, Dept Gastroenterol & Hepatol, Inst Digest Dis, Cleveland, OH 44106 USA Cleveland Clin, Lerner Res Inst, Dept Pathobiol, Cleveland, OH 44106 USA Sahlgrens Acad, Inst Med, Dept Internal Med, Gothenburg, Sweden Univ Hosp, Gothenburg, Sweden Univ Paris 06, Hop St Antoine, AP HP, Dept Hepatol, Paris, France Univ Calif Davis, Div Gastroenterol & Hepatol, Davis, CA 95616 USA Katholieke Univ Leuven Hosp, Dept Gastroenterol, Louvain, Belgium Univ Med Greifswald, Dept Bioinformat, Inst Biometr & Med Informat, Greifswald, Germany Univ Montreal, Res Ctr, Montreal, PQ, Canada Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada Univ Cambridge, Dept Med, Div Hepatol, Cambridge CB2 2QQ, England Karolinska Univ, Huddinge Hosp, Karolinska Inst, Dept Gastroenterol & Hepatol, Stockholm, Sweden Yale Univ, Dept Med, Sect Digest Dis, New Haven, CT 06520 USA Univ Kiel, Dept Gen Internal Med, Kiel, Germany Univ Kiel, Univ Hosp Schleswig Holstein, PopGen Biobank, Kiel, Germany Helsinki Univ Hosp, Dept Med, Div Gastroenterol, Helsinki, Finland Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA John Radcliffe Univ Hosp NHS Trust, Dept Hepatol, Oxford, England Univ Bergen, Dept Clin Med, Div Gastroenterol, Bergen, Norway, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology
Subjects: Linkage disequilibrium, HISTONE DEACETYLASE, Genotyping Techniques, endocrine system diseases, Genome-wide association study, Disease, Bioinformatics, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Risk Factors, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Crohn's disease, education.field_of_study, digestive, oral, and skin physiology, CELIAC-DISEASE, Genetic Pleiotropy, Lifrarsjúkdómar, 3. Good health, FALSE DISCOVERY RATE, ULCERATIVE-COLITIS, genetic association study, disease genetics, 030211 gastroenterology & hepatology, SUSCEPTIBILITY LOCI, Population, Cholangitis, Sclerosing, Single-nucleotide polymorphism, Human leukocyte antigen, GENETIC RISK, Biology, liver, Polymorphism, Single Nucleotide, digestive system, Article, Primary sclerosing cholangitis, 03 medical and health sciences, FUNCTIONAL SIMILARITY, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, NATURAL-HISTORY, Arfgengi, medicine.disease, digestive system diseases, immunogenetics, Genetic Loci, Case-Control Studies, Immunology, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases. Norwegian PSC Research Center German Ministry of Education and Research through the National Genome Research Network 01GS0809-GP7 Deutsche Forschungsgemeinschaft FR 2821/2-1 Integrated Research and Treatment Center-Transplantation 01EO0802 PopGen Biobank Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/262055
Published: 2013
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49. Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation

Author: Luca Jovine, Thomas Schwend, C. Finta, A.L. Cherry, Juan Astorga-Wells, M. Karlstrom, Daniele de Sanctis, M. Del Campo, Qianren Jin, R. Toftgard, Angela Criswell, Roman A. Zubarev, Karolinska Inst, Novum, Ctr Biosci, SE-14183 Huddinge, Sweden, Karolinska Inst, Novum, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden, Biomotif AB, SE-18212 Danderyd, Sweden, Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden, Rigaku Amer Corp, The Woodlands, TX 77381 USA, European Synchrotron Radiation Facility (ESRF), and Cherry, Amy L
Subjects: Models, Molecular, Hedgehog signalling regulation, animal structures, SUFU, Protein Conformation, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Repressor, Biology, Crystallography, X-Ray, Zinc Finger Protein GLI1, 03 medical and health sciences, QH301, 0302 clinical medicine, Protein structure, Structural Biology, Animals, Humans, Amino Acid Sequence, Protein Interaction Maps, Peptide sequence, Transcription factor, 030304 developmental biology, Genetics, 0303 health sciences, Cell growth, General Medicine, Research Papers, Cell biology, Repressor Proteins, Hedgehog signalling, Hedgehogs, 030220 oncology & carcinogenesis, embryonic structures, Signal transduction, Intracellular, Signal Transduction, Transcription Factors, GLI
Abstract: Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation., Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.
Published: 2013
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50. Re: A Structured Interdomain Linker Directs Self-Polymerization of Human Uromodulin

Author: Luca Rampoldi, Luca Jovine, K. Nishimura, Martina Brunati, Ling Han, Marcel Bokhove, Daniele de Sanctis, Bokhove, M, Nishimura, K, Brunati, M, Han, L, de Sanctis, D, Rampoldi, L, Jovine, L, Karolinska Inst, Ctr Innovat Med, SE-14183 Huddinge, Sweden, Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden, Ist Sci San Raffaele, Div Genet & Cell Biol, Mol Genet Renal Disorders Unit, I-20132 Milan, Italy, and European Synchrotron Radiation Facility (ESRF)
Subjects: Models, Molecular, 0301 basic medicine, Tamm–Horsfall protein, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Fluorescent Antibody Technique, Crystallography, X-Ray, Madin Darby Canine Kidney Cells, Polymerization, Mice, 0302 clinical medicine, Medicine, Disulfides, TECTA, chemistry.chemical_classification, Extracellular Matrix Proteins, education.field_of_study, Multidisciplinary, biology, Sperm receptor, Biological Sciences, Cell biology, Biochemistry, ZP2, Recombinant Fusion Proteins, Urology, Blotting, Western, Molecular Sequence Data, Mutation, Missense, Computational biology, GPI-Linked Proteins, Maltose-Binding Proteins, 03 medical and health sciences, Dogs, Uromodulin, Animals, Humans, Amino Acid Sequence, education, Gene, X-ray crystallography, Innate immune system, zona pellucida domain, business.industry, Protein Structure, Tertiary, HEK293 Cells, 030104 developmental biology, chemistry, Structural Homology, Protein, biology.protein, Protein Multimerization, Glycoprotein, business, Sequence Alignment, Linker, 030217 neurology & neurosurgery, Function (biology)
Abstract: International audience; Uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant human urinary protein, plays a key role in chronic kidney diseases and is a promising therapeutic target for hypertension. Via its bipartite zona pellucida module (ZP-N/ZP-C), UMOD forms extracellular filaments that regulate kidney electrolyte balance and innate immunity, as well as protect against renal stones. Moreover, salt-dependent aggregation of UMOD filaments in the urine generates a soluble molecular net that captures uropathogenic bacteria and facilitates their clearance. Despite the functional importance of its homopolymers, no structural information is available on UMOD and how it self-assembles into filaments. Here, we report the crystal structures of polymerization regions of human UMOD and mouse ZP2, an essential sperm receptor protein that is structurally related to UMOD but forms heteropolymers. The structure of UMOD reveals that an extensive hydrophobic interface mediates ZP-N domain homodimerization. This arrangement is required for filament formation and is directed by an ordered ZP-N/ZP-C linker that is not observed in ZP2 but is conserved in the sequence of deafness/Crohn's disease-associated homopolymeric glycoproteins a-tectorin (TECTA) and glycoprotein 2 (GP2). Our data provide an example of how interdomain linker plasticity can modulate the function of structurally similar multidomain proteins. Moreover, the architecture of UMOD rationalizes numerous pathogenic mutations in both UMOD and TECTA genes
Published: 2016
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