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1. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Author

Scott RA, Fall T, Pasko D, Barker A, Sharp SJ, Arriola L, Balkau B, Barricarte A, Barroso I, Boeing H, Clavel Chapelon F, Crowe FL, Dekker JM, Fagherazzi G, Ferrannini E, Forouhi NG, Franks PW, Gavrila D, Giedraitis V, Grioni S, Groop LC, Kaaks R, Key TJ, Kühn T, Lotta LA, Nilsson PM, Overvad K, Palli D, Quirós JR, Rolandsson O, Roswall N, Sacerdote C, Sala N, Sánchez MJ, Schulze MB, Siddiq A, Slimani N, Sluijs I, Spijkerman AM, Tjonneland A, Tumino R, van der A. DL, Yaghootkar H, RISC Study Group, EPIC InterAct Consortium, McCarthy MI, Semple RK, Riboli E, Walker M, Ingelsson E, Frayling TM, Savage DB, Langenberg C, Wareham N.J., PANICO, SALVATORE, Sharp, Stephen [0000-0003-2375-1440], Barroso, Ines [0000-0001-5800-4520], Forouhi, Nita [0000-0002-5041-248X], Semple, Robert [0000-0001-6539-3069], Savage, David [0000-0002-7857-7032], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Scott, Ra, Fall, T, Pasko, D, Barker, A, Sharp, Sj, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel Chapelon, F, Crowe, Fl, Dekker, Jm, Fagherazzi, G, Ferrannini, E, Forouhi, Ng, Franks, Pw, Gavrila, D, Giedraitis, V, Grioni, S, Groop, Lc, Kaaks, R, Key, Tj, Kühn, T, Lotta, La, Nilsson, Pm, Overvad, K, Palli, D, Panico, Salvatore, Quirós, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, Mj, Schulze, Mb, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, Am, Tjonneland, A, Tumino, R, van der A., Dl, Yaghootkar, H, RISC Study, Group, EPIC InterAct, Consortium, Mccarthy, Mi, Semple, Rk, Riboli, E, Walker, M, Ingelsson, E, Frayling, Tm, Savage, Db, Langenberg, C, and Wareham, N. J.

Subjects
Adult, Male, Genetic Variation, Alanine Transaminase, gamma-Glutamyltransferase, Glucose Tolerance Test, Middle Aged, Overweight, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, Diabetes Mellitus, Type 2, Insulin Secretion, Body Composition, Glucose Clamp Technique, Body Fat Distribution, Humans, Insulin, Female, Genetic Predisposition to Disease, Obesity, Insulin Resistance, Waist Circumference, Aged
Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Published
2014

2. Postcranial morphology of the middle Pleistocene humans from Sima de los Huesos, Spain

Author

Arsuaga, J.L., Carretero, J.M, Lorenzo, C., Gómez-Olivencia, A., Pablos, A., Rodríguez, L., García-González, R., Bonmatí, A., Qua, R.M., Pantoja-Pérez, A., Martínez, I., Aranburu, A., Gracia-Téllez, A., Poza-Rey, E., Sala, N., García, N., De Velasco, A.A., Cuenca-Bescós, G., De Castro, J.M.B., and Carbonell, E.

Subjects
Fossils, postcranial anatomy, Population Dynamics, Skull, Paleontology, Hominidae, phylogeny, Body Height, Bone and Bones, human evolution, Spain, bauplan, Animals, Body Size, Humans, Sierra de Atapuerca, Neanderthals
Abstract

Current knowledge of the evolution of the postcranial skeleton in the genus Homo is hampered by a geographically and chronologically scattered fossil record. Here we present a complete characterization of the postcranium of the middle Pleistocene paleodeme from the Sima de los Huesos (SH) and its paleobiological implications. The SH hominins show the following: (i) wide bodies, a plesiomorphic char- acter in the genus Homo inherited from their early hominin ancestors; (ii) statures that can be found in modern human middle-latitude pop- ulations that first appeared 1.6–1.5 Mya; and (iii) large femoral heads in some individuals, a trait that first appeared during the middle Pleistocene in Africa and Europe. The intrapopulational size variation in SH shows that the level of dimorphism was similar to modern humans (MH), but the SH hominins were less encephalized than Ne- andertals. SH shares many postcranial anatomical features with Ne- andertals. Although most of these features appear to be either plesiomorphic retentions or are of uncertain phylogenetic polarity, a few represent Neandertal apomorphies. Nevertheless, the full suite of Neandertal-derived features is not yet present in the SH popula- tion. The postcranial evidence is consistent with the hypothesis based on the cranial morphology that the SH hominins are a sister group to the later Neandertals. Comparison of the SH postcranial skeleton to other hominins suggests that the evolution of the postcranium oc- curred in a mosaic mode, both at a general and at a detailed level.

Published
2016

3. Protein S deficiency: a database of mutations--summary of the first update

Author

Aiach M, Bernardi F, Delphine Borgel, Dn, Cooper, Espinosa-Parrilla Y, Formstone C, Gandrille S, Lind B, Mannhalter C, Pabinger I, Ph, Reitsma, Rezende S, Saito H, Sala N, Simmonds R, Suzuki K, and Other departments

Subjects
Protein S Deficiency, Databases, Factual, Mutation, Humans
Published
2000

4. Ectopic transcript analysis indicates that allelic exclusion is an important cause of type I protein C deficiency in patients with nonsense and frameshift mutations in the PROC gene

Author

Jm, Soria, Lp, Berg, Fontcuberta J, Vv, Kakkar, Xavier Estivill, Dn, Cooper, and Sala N

Subjects
Male, Blood Protein Disorders, DNA, Complementary, Transcription, Genetic, Spain, Humans, Protein C Deficiency, Female, RNA, Messenger, Frameshift Mutation, Alleles, Pedigree, Protein C
Abstract

Nonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through "allelic exclusion" at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3' to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons.

Published
1996

5. Absence of linkage between type III protein S deficiency and the PROS1 and C4BP genes in families carrying the protein S Heerlen allele

Author

Espinosa-Parrilla, Y., Morell, M., Souto, J. C., Borrell, M., Damian Heine Suñer, Tirado, I., Volpini, V., Estivill, X., and Sala, N.

Subjects
Adult, Male, Protein S Deficiency, Genotype, Integrin alphaXbeta2, Proteins, Linkage Disequilibrium, Pedigree, Humans, Point Mutation, Female, Chromosomes, Human, Pair 3, Carrier Proteins, Complement Activation, Alleles
Abstract

To elucidate the molecular basis of hereditary protein S (PS) deficiency and, in particular, type III or free PS deficiency, the allelic distribution and segregation patterns of the PS gene (PROS1) polymorphisms P626A/G and S460P (PS Heerlen) have been analyzed in a group of 45 proposita suffering from type I or type III PS deficiency. No differences between patients and controls were found in the frequency of the P626A/G alleles. By contrast, the frequency of the PS Heerlen allele in the group of patients with type III PS deficiency (9 of 46 chromosomes, P = .196) was significantly higher (P.001) than in the control group (1 of 300 chromosomes, P = .003). The A allele of P626A/G was always associated with the P allele of S460P. However, this haplotype did not co-segregate with the type III PS-deficient phenotype in 3 of the families. Furthermore, multipoint linkage analysis excluded the whole PROS1 gene in 1 of these families, which is in agreement with the absence of mutations in the PROS1 gene, as determined by sequence analysis. Finally, linkage analysis with 4 microsatellite markers linked to the C4BPB and C4BPA loci also excluded these two genes. From these results we conclude that, at least in some families, the molecular basis of type III PS deficiency is not due to the Mendelian inheritance of a single defect in the PROS1 or in the C4BP genes.

6. [Polymorphism MI detected through the enzyme MspI in the study of congenital protein C deficiency]

Author

Jm, Soria, Ibáñez I, Fontcuberta J, Borrell M, Xavier Estivill, and Sala N

Subjects
Polymorphism, Genetic, Pregnancy, Prenatal Diagnosis, Carrier State, Humans, Protein C Deficiency, Female, DNA, Blood Coagulation Disorders, Deoxyribonucleases, Type II Site-Specific, Alleles, Deoxyribonuclease HpaII
Abstract

In order to find alternatives for the diagnosis of hereditary protein C (PC) deficiency, we have studied the diagnostic informativity of the restriction fragment length polymorphism (RFLP) MI, located 7 kb upstream of the PC gene and detected with the restriction enzyme MspI.The RFLP MI has been analysed in 77 individuals belonging to 27 families with congenital PC deficiency, as well as in a control group of 46 healthy donors. The analysis has been performed by PCR amplification and MspI digestion of the polymorphic DNA fragment.The allelic frequencies of the RFLP MI in the population studied are 0.69 for the allele A1, without the MspI restriction site, and 0.31 for the allele A2, with the MspI site. No differences have been found between the control and the PC deficient groups. The informativity of the polymorphism has been calculated to be 33.8%. Consegregation studies between this RFLP and PC deficiency have allowed the determination of the allele associated to the polymorphism in 21 out of the 27 studied families. Furthermore, an asymptomatic PC deficient carrier, with normal PC levels, has been identified.The study of this RFLP in families with hereditary PC deficiency may be useful for the identification of PC deficient carriers as well as for the prenatal diagnosis of the deficiency.

7. Development and validation of a lifestyle-based model for colorectal cancer risk prediction: the LiFeCRC score

Author

Amanda J. Cross, Kristin Benjaminsen Borch, Anne Kirstine Eriksen, Elio Riboli, José María Huerta, H. Bas Bueno-de-Mesquita, Giovanna Masala, Núria Sala, Anne Tjønneland, Anika Hüsing, Rudolf Kaaks, Sara Grioni, Anne M. May, Fanny Artaud, Antonia Trichopoulou, Pilar Amiano, Eleni Peppa, Marc J. Gunter, Timothy J. Key, Aurelio Barricarte Gurrea, Jonna Berntsson, Anna Karakatsani, Mazda Jenab, Elisabete Weiderpass, Isabel Drake, Christina C. Dahm, Torkjel M. Sandanger, Bethany Van Guelpen, Robin Reichmann, María José Sánchez, Guri Skeie, Konstantinos K. Tsilidis, Gianluca Severi, Carlotta Sacerdote, Sjoerd G. Elias, José Ramón Quirós, Marie-Christine Boutron-Ruault, Salvatore Panico, Krasimira Aleksandrova, Rosario Tumino, Sophia Harlid, Elom K. Aglago, [Aleksandrova,K, Reichmann,R] Nutrition, Immunity and Metabolism Senior Scientist Group, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany. [Aleksandrova,K, Reichmann,R] Institute of Nutritional Science, University of Potsdam, Potsdam, Germany. [Aleksandrova,K] Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany. [Kaaks,R, Hüsing,A] Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Jenab,M, Weiderpass,E, Aglago,EK, Gunter,MJ] International Agency for Research on Cancer, World Health Organization, Lyon, France. [Bueno-de-Mesquita,HB] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [Bueno-de-Mesquita,HB, Cross,AJ, Tsilidis,KK, Riboli,E] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. [Dahm,CC] Department of Public Health, Aarhus University, Aarhus, Denmark. [Eriksen,AK, Tjønneland,A] Danish Cancer Society Research Center, Copenhagen, Denmark. [Artaud,F, Boutron-Ruault,MC, Severi,G] CESP, Faculté de Medicine, Université Paris-Saclay, Villejuif, France. [Artaud,F, Severi,G] Institut Gustave Roussy, Villejuif, France. [Severi,G] Dipartimento di Statistica, Informatica e Applicazioni 'G. Parenti' (DISIA), University of Florence, Florence, Italy. [Trichopoulou,A, Karakatsani,A, Peppa,E] Hellenic Health Foundation, Athens, Greece. [Karakatsani,A] 2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, 'ATTIKON' University Hospital, Haidari, Greece. [Panico,S] EPIC Centre of Naples, Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy. [Masala,G] 1Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network – ISPRO, Florence, Italy. [Grioni,S] Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. [Sacerdote,C] Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy. [Tumino,R] Cancer Registry and Histopathology Department, Provincial Health Authority (ASP), Ragusa, Italy. [Elias,SG, May,AM] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. [Borch,KB, Sandanger,TM, Skeie,G] Department of Community Medicine, Health Faculty, UiT-the Arctic university of Norway, Tromsø, Norway. [Sánchez,MJ] Escuela Andaluza de Salud Pública (EASP), Granada, Spain. [Sánchez,MJ] Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain. [Sánchez,MJ, Huerta,JM, Gurrea,AB, Amiano,P] Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. [Sánchez,MJ] Universidad de Granada, Granada, Spain. [Huerta,JM] Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain. [Sala,N] Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Barcelona, Spain. [Sala,N] Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. [Gurrea,AB] Navarra Public Health Institute, Pamplona, Spain. [Gurrea,AB] Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. [Quirós,JR] Public Health Directorate, Asturias, Spain. [Amiano,P] Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain. [Berntsson,J] Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden. [Drake,I] Department of Clinical Sciences in Malmö, Lund University, Lund, Sweden. [van Guelpen,B, Harlid,S] Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden. [van Guelpen,B] Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. [Key,T] Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. [Tsilidis,KK] Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece., This work was supported by the German Research Foundation (DFG) (grant AL 1784/3-1), which funded the research position of Dr. Aleksandrova for organizing study conduct and analysis. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ) and Federal Ministry of Education and Research (BMBF) (Germany), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS), Instituto de salud Carlos III PI13/00061 to Granada, PI13/ 01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236), Navarra and Catalonia (Catalan Institute of Oncology – ICO-IDIBELL) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), and Cancer Research UK (C864/A14136 to EPIC-Norfolk and C8221/A19170 to EPICOxford), Medical Research Council (MR/N003284/1 and MC-UU_12015/1 to EPIC-Norfolk and MR/M012190/1 to EPIC-Oxford) (United Kingdom). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Open Access funding enabled and organized by Projekt DEAL.

Subjects
Male, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Health Care Evaluation Mechanisms::Statistics as Topic::Probability::Risk::Risk Assessment [Medical Subject Headings], lcsh:Medicine, Cancer prevention, Cohort Studies, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Calibration [Medical Subject Headings], 0302 clinical medicine, Risk Factors, Neoplasias colorrectales, Medicine, 030212 general & internal medicine, Prospective Studies, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Nutritional Status [Medical Subject Headings], 10. No inequality, Prospective cohort study, 11 Medical and Health Sciences, Framingham Risk Score, Risk screening, Lifestyle behaviour, Risk prediction, Colorectal cancer, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, 030220 oncology & carcinogenesis, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Health Care Evaluation Mechanisms::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Prospective Studies [Medical Subject Headings], Female, Risk assessment, Colorectal Neoplasms, Research Article, Cohort study, Estils de vida, Waist, Lifestyles, Nutritional Status, Check Tags::Male [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet [Medical Subject Headings], Estil de vida, Risk Assessment, Riesgo, Estilo de vida, 03 medical and health sciences, Càncer colorectal, General & Internal Medicine, Humans, Life Style, business.industry, lcsh:R, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Health Care Evaluation Mechanisms::Statistics as Topic::Probability::Risk [Medical Subject Headings], Technology and Food and Beverages::Food and Beverages::Food::Vegetables [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [Medical Subject Headings], Psychiatry and Psychology::Behavior and Behavior Mechanisms::Psychology, Social::Life Style [Medical Subject Headings], Nomogram, Lifestyle, Diet, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Check Tags::Female [Medical Subject Headings], Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Movement::Motor Activity::Exercise [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], business, Prevención de Enfermedades, Demography
Abstract

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992–2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell’s C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264–0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084–0.575)). Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level., German Research Foundation (DFG) AL 1784/3-1, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain) 6236, Regional Government of Navarra (Spain), Regional Government of Catalonia (Catalan Institute of Oncology -ICO-IDIBELL) (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK C864/A14136 C8221/A19170, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/N003284/1 MC-UU_12015/1 MR/M012190/1, Projekt DEAL

Published
2021

8. The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk

Author

Olga M. Sinilnikova, Rudolf Kaaks, Pilar Amiano, Anne Tjønneland, José Ramón Quirós, Eiliv Lund, Daniele Campa, Carla H. van Gils, Göran Hallmans, Kay-Tee Khaw, H. Bas Bueno-de-Mesquita, Anika Hüsing, Sabina Rinaldi, Nicholas J. Wareham, Nathalie Chabbert-Buffet, Kim Overvad, Eva Ardanaz, Sabine Rohrmann, Vittorio Krogh, Federico Canzian, Giovanna Masala, Françoise Clavel-Chapelon, María Dolores Chirlaque, Per Lenner, Carlotta Sacerdote, Esther Molina-Montes, Guy Fagherazzi, Jakob Stegger, James McKay, N. Charlotte Onland-Moret, Salvatore Panico, Rosario Tumino, Afshan Siddiq, Birgit Teucher, Timothy J. Key, Erifili Oustoglou, Ruth C. Travis, Veronique Chajes, Dimosthenis Zylis, Ulla Vogel, Antonia Trichopoulou, Elio Riboli, Nadia Slimani, Heiner Boeing, Núria Sala, Eva Fisher, Wareham, Nicholas [0000-0003-1422-2993], Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, Campa, D, Hüsing, A, Mckay, Jd, Sinilnikova, O, Vogel, U, Tjønneland, A, Overvad, K, Stegger, J, Clavel Chapelon, F, Chabbert Buffet, N, Fagherazzi, G, Trichopoulou, A, Zylis, D, Oustoglou, E, Rohrmann, S, Teucher, B, Fisher, E, Boeing, H, Masala, G, Krogh, V, Sacerdote, C, Panico, Salvatore, Tumino, R, Onland Moret, Nc, van Gils, Ch, Bueno de Mesquita, Hb, Lund, E, Chirlaque, Md, Sala, N, Quirós, Jr, Ardanaz, E, Amiano, P, Molina Montes, E, Hallmans, G, Lenner, P, Travis, Rc, Key, Tj, Wareham, N, Khaw, Kt, Rinaldi, S, Slimani, N, Chajes, V, Siddiq, A, Riboli, E, Kaaks, R, Canzian, F., and [Campa D, Hüssing A, Rohrmann S, Teucher B, Kaaks R, Canzian F] German Cancer Research Center (DKFZ), Heidelberg, Germany. [McKay JD, Slimani N, Chajes V] International Agency for Research on Cancer, Lyon, France. [Sinilnikova O] Hospices Civils de Lyon/Centre Léon Bérard, UMR5201 CNRS-Université Claude Bernard, Lyon, France. [Vogel U] National Food Institute Technical University of Denmark, Denmark. [Tjønneland A] Danish Cancer Society, Copenhagen, Denmark. [Overvad K] Aarhus University Hospital, Aalborg, Denmark. [Stegger J] Department of Cardiology, Cardiovascular Research Centre, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark. [Clavel-Chapelon F, Chabbert-Buffet N, Fagherazzi G] Institut Gustave Roussy, Villejuif, France. [Trichopoulou A, Zylis D] WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. [Trichopoulou A, Oustoglou E] Hellenic Health Foundation, Athens, Greece. [Fisher E, Boeing H] German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany. [Masala G] Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy. [Krogh V] Istituto Nazionale dei Tumori (IRCCS), Milan, Italy. [Sacerdote C] CPO Piemonte, Turin, Italy. [Panico S] Department of Clinical and Experimental Medicine Federico II University, Naples, Italy. [Tumino R] Azienda Ospedaliera 'Civile M.P.Arezzo' Ragusa, Italy. [Onland-Moret NC, van Gils CH] Julius Center, University Medical Center, Utrecht, The Netherlands. [Bueno-de-Mesquita HB] National Institute for Public Health and the Environment, Bilthoven, The Netherlands. [Lund E] Institute of Community Medicine University of Tromsø, Tromsø, Norway. [Chirlaque MD] Murcia Regional Health Council, Murcia, Spain. [Sala N] Catalan Institute of Oncology, Barcelona, Spain. [Quirós JR] Consejería de Salud y Servicios Sanitarios Principado de Asturias, Oviedo, Spain. [Ardanaz E] Public Health Institute of Navarra, Pamplona, Spain. [Amiano P] Public Health Department of Gipuzkoa, San Sebastian, Spain. [Molina-Montes E] Andalusian School of Public Health, Granada, Spain. [Chirlaque MD, Amiano P, Molina-Montes E] CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. [Hallmans G, Lenner2 P] Umeå University, Umeå, Sweden. [Travis RC, Key TJ] Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK OX3 7LF. [Wareham N, Khaw KT] University of Cambridge, Cambridge, UK. [Siddiq A, Riboli E] Imperial College, London, UK.

Subjects
Oncology, Aging, Cancer Research, Genome-wide association study, 32 Biomedical and Clinical Sciences, Body Mass Index, Cohort Studies, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings], 0302 clinical medicine, 2.1 Biological and endogenous factors, membrane protein, POPULATION, Cancer, 2. Zero hunger, 2 Aetiology, 0303 health sciences, education.field_of_study, Intracellular Signaling Peptides and Proteins, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 4203 Health Services and Systems, 3. Good health, Índice de masa muscular, INSIG2 protein, Adipose Tissue, Neoplasias de la mama, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins [Medical Subject Headings], Female, Life Sciences & Biomedicine, Cohort study, Research Article, Adult, Risk, medicine.medical_specialty, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Genotype, Estudios de cohortes, Population, Polimorfismo Genético, COMMON GENETIC VARIANT, PHENOTYPES, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Breast Neoplasms, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, lcsh:RC254-282, Estudio de Asociación del Genoma Completo, 03 medical and health sciences, Breast cancer, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, Breast Cancer, POLYGENIC CONTRIBUTION, medicine, Genetics, Humans, signal peptide, Neoplasm Invasiveness, Obesity, human, education, Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings], 030304 developmental biology, Nutrition, Aged, Science & Technology, Polymorphism, Genetic, Models, Genetic, business.industry, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, Prevention, Case-control study, 42 Health Sciences, Membrane Proteins, DNA, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings], medicine.disease, 3211 Oncology and Carcinogenesis, Health Care::Environment and Public Health::Public Health::Epidemiologic Measurements::Biometry::Anthropometry::Body Mass Index [Medical Subject Headings], VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, Case-Control Studies, Immunology, INSIG2 protein, human, business, Body mass index, Genome-Wide Association Study
Abstract

Background The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC). Methods we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk. Results and Conclusions In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.

Published
2016

9. Sources of pre-analytical variations in yield of DNA extracted from blood samples: analysis of 50,000 DNA samples in EPIC

Author

Domenico Palli, Bertrand Hémon, Petra H.M. Peeters, Guri Skeie, Gilles Ferro, Pierre Hainaut, Françoise Clavel-Chapelon, Karina Standahl Olsen, Amy Hutchinson, Carine Biessy, Elio Riboli, Afshan Siddiq, Antonia Trichopoulou, Pagona Lagiou, Christophe Lallemand, Nicholas J. Wareham, Federico Canzian, Heiner Boeing, Anne Boland, Claudia Agnoli, Roberto Bilbao, Elodie Caboux, Eiliv Lund, Ruth C. Travis, Carmen Navarro, Maimuna Mendy, Núria Sala, Laure Dossus, Eva Fisher, Dimitrios Trichopoulos, Aurelio Barricarte, Yvonne T. van der Schouw, Maria Luisa Redondo, H. Bas Bueno-de-Mesquita, Isabelle Romieu, Rosario Tumino, Marie-Christine Boutron-Ruault, Salvatore Panico, Abigail Britten, Paolo Vineis, Silvia Polidoro, Mark J. Gunter, Sabina Rinaldi, María José Sánchez, Matthew A. Sims, International Prevention Research Institute (IPRI), Caboux, E, Lallemand, C, Ferro, G, H?mon, B, Mendy, M, Biessy, C, Sims, M, Wareham, N, Britten, A, Boland, A, Hutchinson, A, Siddiq, A, Vineis, P, Riboli, E, Romieu, I, Rinaldi, S, Gunter, Mj, Peeters, Ph, van der Schouw, Yt, Travis, R, Bueno de Mesquita, Hb, Canzian, F, S?nchez, Mj, Skeie, G, Olsen, K, Lund, E, Bilbao, R, Sala, N, Barricarte, A, Palli, D, Navarro, C, Panico, Salvatore, Redondo, Ml, Polidoro, S, Dossus, L, Boutron Ruault, Mc, Clavel Chapelon, F, Trichopoulou, A, Trichopoulos, D, Lagiou, P, Boeing, H, Fisher, E, Tumino, R, Agnoli, C, Hainaut, P., [Caboux,E, Lallemand,C, Ferro,G, Hémon,B, Mendy,M, Biessy,C, Romieu,I, Rinaldi,S] International Agency for Research on Cancer, Lyon, France. [Sims,M, Wareham,N, Britten,A] Medical Research Council (MRC) Epidemiology Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom. [Boland,A] Centre National de Génotypage, Institut Génomique, Commissariat à l’énergie Atomique, Evry, France. [Hutchinson,A] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, Maryland, United States of America. [Siddiq,A, Vineis,P, Riboli,E, Gunter,MJ, Peeters,PHM] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom. [Peeters,PHM, Schouw,T] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. [Travis,R[ Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. [Bueno-de-Mesquita,HB] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. [Canzian,F] Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Sánchez,M] Andalusian School of Public Health, Granada (Spain) and CIBER de Epidemiología y Salud Pública (CIBERESP), Granada, Spain. [Skeie,G, Olsen,KS, Lund,E] Institute of Community Medicine, University of Tromsø, Tromsø, Norway. [Bilbao,R] Fundación Vasca de Innovación e Investigación Sanitarias, Sondika, Bizkaia, Spain. [Sala,N] Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain. [Barricarte,A] Navarre Public Health Institute, Pamplona, Spain. [Barricarte,A, Navarro,C] Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), Madrid, Spain. [Hainaut,P] International Prevention Research Institute, Lyon, France. [Palli,D] Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Florence, Italy. [Navarro,C] Department of Epidemiology, Regional Health Authority, Murcia, Spain. [Panico,S] Department of clinical and experimental medicine, Federico ii University, Naples, Italy. [Redondo,ML] Public Health Directorate, Asturias, Spain. [Polidoro,S] Human Genetics Foundation-HuGeF, Turin, Italy. [Dossus,L, Boutron-Ruault,MC, Clavel-Chapelon,F] INSERM U1018, Gustave Roussy Institute, Paris South University, Villejuif, France. [Trichopoulou,A, Lagiou,P] Department of Hygiene, Epidemiology and Medical Statistics, Medical School, World Health Organization (WHO) Collaborating Center for Food and Nutrition Policies, University of Athens, Goudi, Athens, Greece. [Trichopoulou,A, Trichopoulos,D] Hellenic Health Foundation, Athens, Greece. [Trichopoulos,D, Lagiou,P] Department of Epidemiology, Harvard School of Public Health, Massachusetts, Boston, United States of America. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [Boeing,H] Potsdam-Rehbrücke Department of Epidemiology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany. [Fisher,E] Administrative Office of the Commission on Genetic Testing Robert Koch-Institute, Berlin, Germany. [Tumino,R] Cancer Registry and Histopathology Unit, ‘‘Civile M. P. Arezzo’’ Hospital, Ragusa, Italy. [Agnoli,C] Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Funding: The study was funded by European Commission Research & Innovation DG project BBMRI (Biobanking and Biomolecular Resources Research Infrastructure,http://www.bbmri.eu), project number 212111 and by the Regular Budget of International Agency for Research on Cancer (IARC). DNA extraction data used in the study were generated as part of molecular epidemiological studies approved by the Steering Committee of the European Prospective Investigation into Cancer and Nutrition (EPIC, http://epic.iarc.fr). Detailed information about the funding of EPIC is available at http://epic.iarc.fr/funding.php. The funding agencies and organizations which provided funds for DNA extraction in specific EPIC studies were Imperial College London (ICL, BRCD study), Medical Research Council UK (MRC UK, EPHD study), European Community INTERACT project (through MRC Cambridge, UK, INT study, http://www.inter-act.eu), International Agency for Research on Cancer (IARC) and Imperial College London (ICL) (LUND study), EU FP6 Network of Excellence Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS, http:// www.ecnis.org), and and Cancer Research UK (CRCUK) (LYMD study).

Subjects
Male, Erythrocytes, Genotyping Techniques, Epidemiology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Errors::Observer Variation [Medical Subject Headings], ADN, Genome-wide association study, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Biochemistry, Body Mass Index, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Anatomy::Cells::Blood Cells::Erythrocytes [Medical Subject Headings], 0302 clinical medicine, Prospective Studies, lcsh:Science, Càncer, Cancer, 0303 health sciences, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Age Factors [Medical Subject Headings], Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Sex Factors [Medical Subject Headings], Genomics, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Specimen Handling [Medical Subject Headings], 3. Good health, SNP genotyping, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Medicine, Cellular Types, Genotyping, Anciano, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Habits::Smoking [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Specimen Handling, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Hemolysis [Medical Subject Headings], 03 medical and health sciences, Cryobiology, AGE, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Genetics, Genome-Wide Association Studies, QUALITY, Humans, Biology, Aged, Science & Technology, Blood Cells, lcsh:R, Computational Biology, DNA, Biotechnology, Check Tags::Female [Medical Subject Headings], Case-Control Studies, Leukocytes, Mononuclear, lcsh:Q, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::DNA [Medical Subject Headings], Índice de Masa Corporal, lcsh:Medicine, Cancer risk, Nucleic Acids, Molecular Cell Biology, GENOME WIDE, RISK, 2. Zero hunger, Observer Variation, Multidisciplinary, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Smoking, Age Factors, Middle Aged, Haemolysis, Nutrition Surveys, CANCER, European Prospective Investigation into Cancer and Nutrition, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Reproducibility of Results [Medical Subject Headings], Multidisciplinary Sciences, CELL COUNT, Genetic Epidemiology, SEX, Female, Research Article, Factores de Edad, Adult, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Clinical Research Design, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Mass Index [Medical Subject Headings], VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, Hemolysis, Adult Age Factors Aged Body Mass Index Case-Control Studies DNA/blood/*isolation & purification Erythrocytes/chemistry Female Genotyping Techniques Hemolysis Humans Leukocytes, Sex Factors, Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Nutrició, 030304 developmental biology, Nutrition, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genotyping Techniques [Medical Subject Headings], Population Biology, business.industry, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear [Medical Subject Headings], Reproducibility of Results, DNA extraction, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Mononuclear/*chemistry Male Middle Aged Observer Variation Prospective Studies Reproducibility of Results Sex Factors Smoking Specimen Handling/*standards, business
Abstract

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies. The study was funded by European Commission Research & Innovation DG project BBMRI (Biobanking and Biomolecular Resources Research Infrastructure, http://www.bbmri.eu), project number 212111 and by the Regular Budget of International Agency for Research on Cancer (IARC). DNA extraction data used in the study were generated as part of molecular epidemiological studies approved by the Steering Committee of the European Prospective Investigation into Cancer and Nutrition (EPIC, http://epic.iarc.fr). Detailed information about the funding of EPIC is available at http://epic.iarc.fr/funding.php. The funding agencies and organizations which provided funds for DNA extraction in specific EPIC studies were Imperial College London (ICL, BRCD study); Medical Research Council UK (MRC UK, EPHD study); European Community INTERACT project (through MRC Cambridge, UK, INT study, http://www.inter-act.eu); International Agency for Research on Cancer (IARC) and Imperial College London (ICL) (LUND study), EU FP6 Network of Excellence Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS, http:// www.ecnis.org); and Cancer Research UK (CRCUK) (LYMD study).

Published
2012

10. Acute or Chronic? A Stressful Question

Author

Paolo Tornese, Maurizio Popoli, Laura Musazzi, N. Sala, Musazzi, L, Tornese, P, Sala, N, and Popoli, M

Subjects
0301 basic medicine, ketamine, media_common.quotation_subject, glutamate, Fight-or-flight response, 03 medical and health sciences, 0302 clinical medicine, stre, Animals, Humans, Chronic stress, Acute stress, resilience, media_common, Neuroscience (all), Mechanism (biology), Animal, General Neuroscience, corticosterone, Stressor, Risk factor (computing), psychopathology, 030104 developmental biology, Acute Disease, Chronic Disease, Psychological, Psychological resilience, Psychology, Stress, Psychological, 030217 neurology & neurosurgery, Psychopathology, Clinical psychology, Human
Abstract

Stress is a primary risk factor for neuropsychiatric disorders; at times, even a single trauma can trigger psychopathology. Many rodent models of neuropsychiatric disorders use chronic stress, measuring readouts at the end of long protocols. In a way, traditional chronic models overlook a crucial question: how does the physiological response to stressor(s) turn into a maladaptive pathway that may verge towards psychopathology? Recent evidence suggests that studying the long-term consequences of acute stress would provide critical information on the role of stress in psychopathology. This new conceptual framework could enable us to understand the determinants of a pro-adaptive versus maladaptive trajectory of stress response, and also to study the mechanism of rapid-acting antidepressants, such as ketamine, that target the glutamate system directly.

Published
2017

11. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Author

Núria Sala, Nina Roswall, Tilman Kühn, Larraitz Arriola, Dorota Pasko, Elio Riboli, Mark I. McCarthy, Afshan Siddiq, María José Sánchez, Luca A. Lotta, Francesca L. Crowe, Timothy J. Key, Peter M. Nilsson, Anne Tjønneland, Inês Barroso, Guy Fagherazzi, Nita G. Forouhi, Carlotta Sacerdote, Kim Overvad, Aurelio Barricarte, Nicholas J. Wareham, Sara Grioni, Tove Fall, Françoise Clavel-Chapelon, Olov Rolandsson, Heiner Boeing, Jacqueline M. Dekker, Mark Walker, Adam Barker, Vilmantas Giedraitis, Daphne L. van der A, Claudia Langenberg, Diana Gavrila, David B. Savage, Ele Ferrannini, Matthias B. Schulze, Hanieh Yaghootkar, Nadia Slimani, Paul W. Franks, Erik Ingelsson, Annemieke M.W. Spijkerman, Robert A. Scott, Ivonne Sluijs, Rosario Tumino, Stephen J. Sharp, Salvatore Panico, Robert K. Semple, Beverley Balkau, Leif Groop, Domenico Palli, Timothy M. Frayling, J. Ramón Quirós, Rudolf Kaaks, Scott, Ra, Fall, T, Pasko, D, Barker, A, Sharp, Sj, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel Chapelon, F, Crowe, Fl, Dekker, Jm, Fagherazzi, G, Ferrannini, E, Forouhi, Ng, Franks, Pw, Gavrila, D, Giedraitis, V, Grioni, S, Groop, Lc, Kaaks, R, Key, Tj, K?hn, T, Lotta, La, Nilsson, Pm, Overvad, K, Palli, D, Panico, Salvatore, Quir?s, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, S?nchez, Mj, Schulze, Mb, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, Am, Tjonneland, A, Tumino, R, van der A., Dl, Yaghootkar, H, Mccarthy, Mi, Semple, Rk, Riboli, E, Walker, M, Ingelsson, E, Frayling, Tm, Savage, Db, Langenberg, C, Wareham, Nj, The RISC The study group InterAct, Consortium, Epidemiology and Data Science, and EMGO - Lifestyle, overweight and diabetes

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, Overweight, Polymorphism, Single Nucleotide, Article, Body Mass Index, Cohort Studies, Insulin resistance, Diabetes mellitus, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Body Fat Distribution, Humans, Insulin, Genetic Predisposition to Disease, Obesity, Aged, 2. Zero hunger, Glucose tolerance test, medicine.diagnostic_test, business.industry, nutritional and metabolic diseases, Genetic Variation, Alanine Transaminase, gamma-Glutamyltransferase, Glucose clamp technique, Glucose Tolerance Test, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Body Composition, Glucose Clamp Technique, Female, medicine.symptom, Insulin Resistance, Waist Circumference, business
Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp– and oral glucose tolerance test–based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], −0.03 [−0.04, −0.01]; P = 0.004). This score was associated with lower BMI (−0.01 [−0.01, −0.0]; P = 0.02) and gluteofemoral fat mass (−0.03 [−0.05, −0.02; P = 1.4 × 10−6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Published
2016

12. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

Nathaniel Rothman, Yolanda Benavente, Paul Brennan, Qing Lan, Pierluigi Cocco, Simon Crouch, Anneclaire J. De Roos, Josh Wright, Christine F. Skibola, Mark P. Purdue, Elisabete Weiderpass, James R. Cerhan, Randy D. Gascoyne, Maria Grazia Ennas, Kari E. North, Zhaoming Wang, Jinyan Huang, Julie M. Cunningham, Alain Monnereau, Peter Kraft, Patricia Hartge, Edward Giovannucci, Karen Curtin, Giovanna Masala, Jacqueline Clavel, Neil E. Kay, Jacques Riby, María Dolores Chirlaque, John J. Spinelli, Delphine Casabonne, Jenny Turner, Lucia Conde, Lesley F. Tinker, Martha Glenn, Sara S. Strom, Donna K. Arnett, Rebecca Montalvan, Ju-Hyun Park, Melissa C. Southey, Ann Maria, Karin E. Smedby, Lindsay M. Morton, Marc Maynadié, Laurie Burdett, Amy Hutchinson, Bengt Glimelius, W. Ryan Diver, Elio Riboli, Sonja I. Berndt, Lisa A. Cannon-Albright, Kimberly A. Bertrand, Aaron D. Norman, Sara J. Achenbach, Celine M. Vachon, Angela Cox, Xifeng Wu, Theodore R. Holford, Neil E. Caporaso, Joseph F. Fraumeni, Roel Vermeulen, Rudolph Kaaks, Mads Melbye, Joseph Vijai, Kari G. Chaffee, Lauren R. Teras, Rebecca D. Jackson, Lenka Foretova, J. Brice Weinberg, Paige M. Bracci, Sophia S. Wang, Demetrius Albanes, Stephen J. Chanock, Wendy Cozen, Mark Liebow, Anne J. Novak, Hans-Olov Adami, George J. Weiner, Angela Brooks-Wilson, Kenneth Offit, Anne Kricker, Claire M. Vajdic, James McKay, Ellen T. Chang, Baoshan Ma, Cristine Allmer, Susan L. Slager, Brian K. Link, Elizabeth A. Holly, Anthony Staines, Liming Liang, Jarmo Virtamo, Timothy G. Call, Nicola J. Camp, Ruth C. Travis, Alexandra Nieters, Degui Zhi, Brenda M. Birmann, Tait D. Shanafelt, Rachel S. Kelly, Graham G. Giles, Nilanjan Chatterjee, John A. Snowden, Yuanqing Ye, Núria Sala, Tongzhang Zheng, Paolo Boffetta, Lynn R. Goldin, Danylo J. Villano, Jose F. Leis, Paolo Vineis, Lucia Miligi, Jian Gu, Justin M. Leach, Silvia de Sanjosé, Richard K. Severson, Yawei Zhang, Henrik Hjalgrim, Roger L. Milne, Charles E. Lawrence, Meredith Yeager, Moara Machado, Nikolaus Becker, Joseph M. Connors, Anne Zeleniuch-Jacquotte, Giovanni Maria Ferri, Stephanie J. Weinstein, LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Berndt, S.I., Camp, N.J., Skibola, C.F., Vijai, J., Wang, Z., Gu, J., Nieters, A., Kelly, R.S., Smedby, K.E., Monnereau, A., Cozen, W., Cox, A., Wang, S.S., Lan, Q., Teras, L.R., Machado, M., Yeager, M., Brooks-Wilson, A.R., Hartge, P., Purdue, M.P., Birmann, B.M., Vajdic, C.M., Cocco, P., Zhang, Y., Giles, G.G., Zeleniuch-Jacquotte, A., Lawrence, C., Montalvan, R., Burdett, L., Hutchinson, A., Ye, Y., Call, T.G., Shanafelt, T.D., Novak, A.J., Kay, N.E., Liebow, M., Cunningham, J.M., Allmer, C., Hjalgrim, H., Adami, H.-O., Melbye, M., Glimelius, B., Chang, E.T., Glenn, M., Curtin, K., Cannon-Albright, L.A., Diver, W.R., Link, B.K., Weiner, G.J., Conde, L., Bracci, P.M., Riby, J., Arnett, D.K., Zhi, D., Leach, J.M., Holly, E.A., Jackson, R.D., Tinker, L.F., Benavente, Y., Sala, N., Casabonne, D., Becker, N., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Chaffee, K.G., Achenbach, S.J., Vachon, C.M., Goldin, L.R., Strom, S.S., Leis, J.F., Weinberg, J.B., Caporaso, N.E., Norman, A.D., De Roos, A.J., Morton, L.M., Severson, R.K., Riboli, E., Vineis, P., Kaaks, R., Masala, G., Weiderpass, E., Chirlaque, M.-D., Vermeulen, R.C.H., Travis, R.C., Southey, M.C., Milne, R.L., Albanes, D., Virtamo, J., Weinstein, S., Clavel, J., Zheng, T., Holford, T.R., Villano, D.J., Maria, A., Spinelli, J.J., Gascoyne, R.D., Connors, J.M., Bertrand, K.A., Giovannucci, E., Kraft, P., Kricker, A., Turner, J., Ennas, M.G., Ferri, G.M., Miligi, L., Liang, L., Ma, B., Huang, J., Crouch, S., Park, J.-H., Chatterjee, N., North, K.E., Snowden, J.A., Wright, J., Fraumeni, J.F., Offit, K., Wu, X., De Sanjose, S., Cerhan, J.R., Chanock, S.J., Rothman, N., Slager, S.L., National Cancer Institute ( NIH ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Registre des hémopathies malignes de Côte d'Or, Mayo Clinic [Rochester], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER-UNICANCER

Subjects
0301 basic medicine, Medicin och hälsovetenskap, Chronic lymphocytic leukemia, General Physics and Astronomy, Genome-wide association study, VARIANTS, Medical and Health Sciences, Malalties hereditàries, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Chronic, Genetics, RISK, Leukemia, Multidisciplinary, BANK1, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Bcl-2-Like Protein 11, Adaptor Proteins, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Single Nucleotide, Lymphocytic, 3. Good health, PRIORITIZATION, Multidisciplinary Sciences, medicine.anatomical_structure, Science & Technology - Other Topics, TRANSCRIPTION FACTOR EOMESODERMIN, Genetic disorders, EXPRESSION, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, FAS GENE-MUTATIONS, Locus (genetics), Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, CLASSIFICATION, White People, Article, 03 medical and health sciences, Proto-Oncogene Proteins, MD Multidisciplinary, medicine, Genetic predisposition, SNP, Humans, Leucèmia limfocítica crònica, Genetic Predisposition to Disease, Polymorphism, B cell, Serpins, Genetic association, Adaptor Proteins, Signal Transducing, Science & Technology, Signal Transducing, B-Cell, Membrane Proteins, General Chemistry, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 030104 developmental biology, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Apoptosis Regulatory Proteins, T-Box Domain Proteins, FOLLICULAR LYMPHOMA, Genome-Wide Association Study
Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P, Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.

Published
2016

13. Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study

Author

Yolanda, Espinosa-Parrilla, Xavier, Muñoz, Catalina, Bonet, Nadia, Garcia, Adoración, Venceslá, Nikos, Yiannakouris, Alessio, Naccarati, Sabina, Sieri, Salvatore, Panico, José M, Huerta, Aurelio, Barricarte, Virginia, Menéndez, Emilio, Sánchez-Cantalejo, Miren, Dorronsoro, Paul, Brennan, Talita, Duarte-Salles, H, B As Bueno-de-Mesquita, Elisabete, Weiderpass, Eiliv, Lund, Françoise, Clavel-Chapelon, Marie-Christine, Boutron-Ruault, Antoine, Racine, Mattijs E, Numans, Rosario, Tumino, Federico, Canzian, Daniele, Campa, Malin, Sund, Mattias, Johansson, Bodil, Ohlsson, Björn, Lindkvist, Kim, Overvad, Anne, Tjønneland, Domenico, Palli, Ruth C, Travis, Kay-Tee, Khaw, Nick, Wareham, Heiner, Boeing, Gabriella, Nesi, Elio, Riboli, Carlos A, Gonzalez, Núria, Sala, Espinosa Parrilla, Y, Mu?oz, X, Bonet, C, Garcia, N, Vencesl?, A, Yiannakouris, N, Naccarati, A, Sieri, S, Panico, Salvatore, Huerta, Jm, Barricarte, A, Men?ndez, V, S?nchez Cantalejo, E, Dorronsoro, M, Brennan, P, Duarte Salles, T, B., As Bueno de Mesquita H, Weiderpass, E, Lund, E, Clavel Chapelon, F, Boutron Ruault, Mc, Racine, A, Numans, Me, Tumino, R, Canzian, F, Campa, D, Sund, M, Johansson, M, Ohlsson, B, Lindkvist, B, Overvad, K, Tj?nneland, A, Palli, D, Travis, Rc, Khaw, Kt, Wareham, N, Boeing, H, Nesi, G, Riboli, E, Gonzalez, Ca, and Sala, N.

Subjects
Male, Chromosomes, Human, X, Adenocarcinoma, Middle Aged, Prognosis, Polymorphism, Single Nucleotide, White People, MicroRNAs, Stomach Neoplasms, Case-Control Studies, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, Chromosomes, Human, Pair 7, Follow-Up Studies, Neoplasm Staging
Abstract

MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.

Published
2014

14. Prostate stem-cell antigen gene is associated with diffuse and intestinal gastric cancer in Caucasians: Results from the EPIC-EURGAST study

Author

Antonia Trichopoulos, Noémie Travier, Mazda Jenab, Domenico Palli, Federico Canzian, María José Sánchez, Rudolf Kaaks, Carlos A. González, Naomi E. Allen, Eric J. Duell, Vittorio Krogh, Kim Overvad, Victor Moreno, G. Johan A. Offerhaus, Núria Sala, Elio Riboli, Salvatore Panico, Jonas Manjer, Petra H.M. Peeters, C. Navarro, Eiliv Lund, M. E. Numans, Françoise Clavel-Chapelon, Ruth C. Travis, Paolo Vineis, Dimosthenis Zylis, Göran Hallmans, Anne Tjønneland, Roger Stenling, Rosario Tumino, Karina Meidtner, Kay-Tee Khaw, Xavier Muñoz, Marie-Christine Boutron-Ruault, Konstantine Tsiotas, Antonio Agudo, Miren Dorronsoro, H. Bas Bueno-de-Mesquita, Heiner Boeing, J. Ramón Quirós, Eva Ardanaz, Sala, N, Muñoz, X, Travier, N, Agudo, A, Duell, Ej, Moreno, V, Overvad, K, Tjonneland, A, Boutron Ruault, Mc, Clavel Chapelon, F, Canzian, F, Kaaks, R, Boeing, H, Meidtner, K, Trichopoulos, A, Tsiotas, K, Zylis, D, Vineis, P, Panico, Salvatore, Palli, D, Krogh, V, Tumino, R, Lund, E, Bueno de Mesquita, Hb, Numans, Me, Peeters, Ph, Quirós, Jr, Sánchez, Mj, Navarro, C, Ardanaz, E, Dorronsoro, M, Hallmans, G, Stenling, R, Manjer, J, Allen, Ne, Travis, Rc, Khaw, Kt, Jenab, M, Offerhaus, Gj, Riboli, E, and González, C. A.

Subjects
Male, Oncology, Cancer Research, Linkage disequilibrium, medicine.medical_specialty, Pathology, Adenocarcinoma, GPI-Linked Proteins, Polymorphism, Single Nucleotide, White People, Helicobacter Infections, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Antigens, Neoplasm, Stomach Neoplasms, Internal medicine, Humans, Medicine, Prospective Studies, Allele, Risk factor, 030304 developmental biology, 0303 health sciences, biology, business.industry, Smoking, Haplotype, Cancer, Middle Aged, Helicobacter pylori, biology.organism_classification, medicine.disease, Neoplasm Proteins, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Case-Control Studies, 030220 oncology & carcinogenesis, Female, business
Abstract

A genome-wide study performed in a Japanese population identified a strong association between SNP rs2294008 (Met1Thr) in the Prostate Stem Cell Antigen gene (PSCA) and diffuse-type gastric cancer (GC). This association was validated in different Asian populations, and, very recently, a study has been published in Caucasians. In this study, we analyzed the association between PSCA variation and GC risk in Caucasians from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Six tagSNPs covering the PSCA gene region were genotyped in 411 incident gastric adenocarcinoma cases and 1530 matched controls from a nested case-control study in the EPIC cohort. Associations were analyzed by unconditional logistic regression, adjusting for age, sex and country. The T allele of rs2294008 in PSCA was found to be a highly significant risk factor for GC (per allele OR = 1.42, 95% CI: 1.23-1.66, p-value = 6.5 × 10(-6) ), particularly of the noncardia-type (per allele OR = 1.47, 95% CI: 1.19-1.81, p-value = 3 × 10(-4) ). At contrast with previous studies, no significant differences were observed between the diffuse (per allele OR = 1.54, 95% CI: 1.20-1.96, p-value = 5 × 10(-4) ) and the intestinal (per allele OR = 1.52, 95% CI: 1.20-1.93, p-value = 5 × 10(-4) ) GC histological subtypes. Although rs12155758 and rs9297976 were also found associated with GC, this association appeared to be due to linkage disequilibrium with rs2294008. Haplotype analysis did not provide additional information. These results confirm the association between variation in the promoter region of PSCA and GC risk in Caucasians and also indicate that the rs2294008 variant is a similar risk factor for both the diffuse and intestinal-types of GC.

Published
2011

15. Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition

Author

Laudina Rodríguez, Steinar Hustad, Carlos A. González, Jonas Manjer, Frederike L. Büchner, Petra H.M. Peeters, Franco Berrino, Kim Overvad, Antonio Agudo, Mario Plebani, Gabriel Capellá, Göran Berglund, Paolo Vineis, Heiner Boeing, Rudolf Kaaks, Fátima Carneiro, Sheila Bingham, Cornelia Weikert, Antonia Trichopoulou, H. Bas Bueno-de-Mesquita, Carmen Enid Martínez, Stein Emil Vollset, Åse Fredriksen, Giuseppe Del Giudice, Simone J. P. M. Eussen, Roger Stenling, Rosario Tumino, Pietro Ferrari, Françoise Clavel-Chapelon, Göran Hallmans, Aurelio Barricarte, Marie-Christine Boutron-Ruault, Nadia Slimani, Sophie Morois, Eiliv Lund, Núria Sala, Elio Riboli, Klaus Meyer, Øivind Midttun, Salvatore Panico, Carmen Navarro, Mattijs E. Numans, Mazda Jenab, Per Magne Ueland, Anne Tjønneland, Larraitz Arrizola, Jakob Linseisen, Domenico Palli, University of Groningen, Eussen, Sj, Vollset, Se, Hustad, S, Midttun, Ø, Meyer, K, Fredriksen, A, Ueland, Pm, Jenab, M, Slimani, N, Ferrari, P, Agudo, A, Sala, N, Capellá, G, Del Giudice, G, Pallid, Boeing, H, Weikert, C, Bueno de Mesquita, Hb, Büchner, Fl, Carneiro, F, Berrino, F, Vineis, P, Tumino, R, Panico, Salvatore, Berglund, G, Manjer, J, Stenling, R, Hallmans, G, Martínez, C, Arrizola, L, Barricarte, A, Navarro, C, Rodriguez, L, Bingham, S, Linseisen, J, Kaaks, R, Overvad, K, Tjønneland, A, Peeters, Ph, Numans, Me, Clavel Chapelon, F, Boutron Ruault, Mc, Morois, S, Trichopoulou, A, Lund, E, Plebanim, Riboli, E, and González, Ca

Subjects
Male, Epidemiology, Atrophic gastritis, Riboflavin, Physiology, Mass Spectrometry, chemistry.chemical_compound, Risk Factors, biology, Middle Aged, FOLATE-DEFICIENCY, European Prospective Investigation into Cancer and Nutrition, Oncology, PERNICIOUS-ANEMIA, METHYLENETETRAHYDROFOLATE-REDUCTASE, Female, medicine.medical_specialty, NUTRIENT INTAKE, UPPER GASTROINTESTINAL-TRACT, Adenocarcinoma, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], Stomach Neoplasms, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Pyridoxal, One-Carbon Group Transferases, ATROPHIC GASTRITIS, business.industry, Case-control study, medicine.disease, HELICOBACTER-PYLORI INFECTION, Vitamin B 6, B vitamins, STOMACH-CANCER, Endocrinology, chemistry, Case-Control Studies, Relative risk, Methylenetetrahydrofolate reductase, HOMOCYSTEINE METABOLISM, MTHFR POLYMORPHISMS, biology.protein, business, Chromatography, Liquid, Blood sampling
Abstract

Contains fulltext : 87498.pdf (Publisher’s version ) (Closed access) B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93

Published
2010

16. Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations

Author

Petra H.M. Peeters, Anne Tjønneland, Philippe Autier, Heiner Boeing, Rudolf Kaaks, Pierre Engel, Françoise Clavel-Chapelon, Fränzel J.B. Van Duijnhoven, James McKay, Anja Olsen, Paolo Vineis, Jakob Linseisen, Aurelio Barricarte, Núria Sala, Elio Riboli, Alina Vrieling, Eva Fisher, Sheila Bingham, Antonia Trichopoulou, Tobias Pischon, Erifili Oustoglou, María Dolores Chirlaque, Graham Byrnes, Miren Dorronsoro, Esther Molina, Hendrik B. Bueno-de-Mesquita, Teresa Norat, Nadia Slimani, Marie-Christine Boutron-Ruault, Pietro Ferrari, Paolo Boffetta, Rosario Tumino, Kay-Tee Khaw, Kim Overvad, Giovanna Masala, Eiliv Lund, Timothy J. Key, Andrew W. Roddam, Mazda Jenab, Eugene Jansen, Göran Hallmans, Sabina Rinaldi, Richard Palmqvist, Vardis Dilis, Franco Berrino, Carla H. van Gils, Magritt Brustad, Laudina Rodríguez Suárez, Amalia Mattiello, Jenab, M., McKay, J., Bueno-De-Mesquita, H.B., Van Duijnhoven, F.J.B., Ferrari, P., Slimani, N., Jansen, E.H.J.M., Pischon, T., Rinaldi, S., Tjønneland, A., Olsen, A., Overvad, K., Boutron-Ruault, M.-C., Clavel-Chapelon, F., Engel, P., Kaaks, R., Linseisen, J., Boeing, H., Fisher, E., Trichopoulou, A., Dilis, V., Oustoglou, E., Berrino, F., Vineis, P., Mattiello, A., Masala, G., Tumino, R., Vrieling, A., Van Gils, C.H., Peeters, P.H., Brustad, M., Lund, E., Chirlaque, M.-D., Barricarte, A., Suárez, L.R., Molina, E., Dorronsoro, M., Sala, N., Hallmans, G., Palmqvist, R., Roddam, A., Key, T.J., Khaw, K.-T., Bingham, S., Boffetta, P., Autier, P., Byrnes, G., Norat, T., and Riboli, E.

Subjects
Male, Oncology, medicine.medical_specialty, Genotype, Epidemiology, Colorectal cancer, Population, Single-nucleotide polymorphism, Calcitriol receptor, White People, Internal medicine, medicine, Vitamin D and neurology, Humans, Genetic Predisposition to Disease, Vitamin D, education, Life Style, education.field_of_study, Polymorphism, Genetic, business.industry, Case-control study, Cancer, Middle Aged, medicine.disease, Vitamin D receptor calcium sensing receptor polymorphisms colorectal cancer European populations, European Prospective Investigation into Cancer and Nutrition, Calcium, Dietary, Europe, Endocrinology, Case-Control Studies, Receptors, Calcitriol, Female, Colorectal Neoplasms, business, Receptors, Calcium-Sensing
Abstract

Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2485-91)

Published
2009

17. DNA repair polymorphisms and the risk of stomach adenocarcinoma and severe chronic gastritis in the EPIC-EURGAST study

Author

Göran Hallmans, Giuseppe Del Giudicce, Carlos Caldas, Eiliv Lund, Francisco Rico, Miren Dorronsoro, Antonio Agudo, Naomi E. Allen, Françoise Clavel-Chapelon, Kim Overvad, Núria Sala, Petra H.M. Peeters, Jakob Linseisen, Rudolf Kaaks, Carmen Martinez, Olof Nyrén, Salvatore Panico, Göran Berglund, H. Bas Bueno-de-Mesquita, Gabriel Capellá, Heiner Boeing, Sheila Bingham, Antonia Trichopoulou, Hendriek C. Boshuizen, Mazda Jenab, Elio Riboli, Gabriele Nagel, Carmen Navarro, Fátima Carneiro, Domenico Palli, Guillem Pera, Henrik Simán, Anne Tjønneland, Mario Plebani, Timothy J. Key, Paolo Vineis, Rosario Tumino, José Ramón Quirós, Mattijs E. Numans, Aurelio Barricarte, Carlos A. González, Franco Berrino, Capellá, G, Pera, G, Sala, N, Agudo, A, Rico, F, Del Giudicce, G, Plebani, M, Palli, D, Boeing, H, Bueno de Mesquita, Hb, Carneiro, F, Berrino, F, Vineis, P, Tumino, R, Panico, Salvatore, Berglund, G, Simán, H, Nyrén, O, Hallmans, G, Martinez, C, Dorronsoro, M, Barricarte, A, Navarro, C, Quirós, Jr, Allen, N, Key, T, Bingham, S, Caldas, C, Linseisen, J, Nagel, G, Overvad, K, Tjonneland, A, Boshuizen, Hc, Peeters, Ph, Numans, Me, Clavel Chapelon, F, Trichopoulou, A, Lund, E, Jenab, M, Kaaks, R, Riboli, E, and González, C. A.

Subjects
Male, DNA Repair, MICROSATELLITE INSTABILITY, Epidemiology, Atrophic gastritis, Colorectal cancer, Chronic gastritis, HOGG1 SER326CYS POLYMORPHISM, CANCER-RISK, LUNG-CANCER, MICROSATELLITE INSTABILITY, INTESTINAL METAPLASIA, CHINESE POPULATION, HELICOBACTER-PYLORI, GENE POLYMORPHISMS, XPD POLYMORPHISMS, COLORECTAL-CANCER, Gastroenterology, COLORECTAL-CANCER, polymorphism, 0302 clinical medicine, Gene Frequency, Pepsinogen A, Odds Ratio, Prospective Studies, 0303 health sciences, HOGG1 SER326CYS POLYMORPHISM, biology, Intestinal metaplasia, Cardia, General Medicine, Middle Aged, Antibodies, Bacterial, 3. Good health, INTESTINAL METAPLASIA, Europe, 030220 oncology & carcinogenesis, Adenocarcinoma, Biological Markers, Female, Gastritis, medicine.symptom, Adult, Gastritis, Atrophic, Risk, medicine.medical_specialty, CANCER-RISK, macromolecular substances, GENE POLYMORPHISMS, Helicobacter Infections, 03 medical and health sciences, LUNG-CANCER, HELICOBACTER-PYLORI, Stomach Neoplasms, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, 030304 developmental biology, Aged, Xeroderma Pigmentosum Group D Protein, CHINESE POPULATION, Polymorphism, Genetic, Helicobacter pylori, business.industry, XPD POLYMORPHISMS, Gastric carcinoma, Microsatellite instability, medicine.disease, biology.organism_classification, Genes, p53, Case-Control Studies, Chronic Disease, business, Biomarkers, H. pylori, genetic susceptibility, Follow-Up Studies
Abstract

BACKGROUND: The contribution of genetic variation in DNA repair genes to gastric cancer (GC) risk remains essentially unknown. The aim of this study was to explore the relative contribution of DNA repair gene polymorphisms to GC risk and severe chronic atrophic gastritis (SCAG). Method A nested case control study within the EPIC cohort was performed including 246 gastric adenocarcinomas and 1175 matched controls. Controls with SCAG (n = 91), as defined by low pepsinogen A (PGA) levels, and controls with no SCAG (n = 1061) were also compared. Twelve polymorphisms at DNA repair genes (MSH2, MLH1, XRCC1, OGG1 and ERCC2) and TP53 gene were analysed. Antibodies against Helicobacter pylori were measured. RESULTS: No association was observed for any of these polymorphisms with stomach cancer risk. However, ERCC2 K751Q polymorphism was associated with an increased risk for non-cardial neoplasm [odds ratio (OR) = 1.78; 95% confidence interval (CI) 1.02-3.12], being ERCC2 K751Q and D312N polymorphisms associated with the diffuse type. ERCC2 D312N (OR = 2.0; 95% CI 1.09-3.65) and K751Q alleles (OR = 1.82; 95% CI 1.01-3.30) and XRCC1 R399Q (OR = 1.69; 95% CI 1.02-2.79) allele were associated with an increased risk for SCAG. CONCLUSION: Our study supports a role of ERCC2 in non-cardial GC but not in cardial cancer. A concordant result was observed for subjects with low PGA levels. XRCC1 allele was associated also with SCAG. This is the first prospective study suggesting that individual variation in DNA repair may be relevant for gastric carcinogenesis, a finding that will require further confirmation validation in larger independent studies. Some authors are partners of ECNIS Network from the 6FP of the EC.

Published
2008

18. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST)

Author

Aurelio Barricarte, J. B.A. Crusius, Eiliv Lund, C. Navarro, G. Del Giudice, J. R. Quirós, P. Ferrari, M. Dorronsoro, Jonas Manjer, Timothy J. Key, S. Rinaldi, Núria Sala, Carmen Martinez, Françoise Clavel-Chapelon, Carlos Caldas, Göran Berglund, Roger Stenling, Göran Hallmans, F. C. Büchner, Domenico Palli, Mario Plebani, H. B. Bueno-de-Mesquita, Rudolf Kaaks, Federico Canzian, P. H. M. Peeters, F. Rico, M. E. Numans, Gabriel Capellá, Fátima Carneiro, Antonia Trichopoulou, Heiner Boeing, A. S. Peña, Naomi E. Allen, Vicki Save, Jakob Linseisen, Valeria Pala, Kim Overvad, S. Binghan, C. A. Gonzalez, Anne Tjønneland, Paolo Vineis, Mazda Jenab, Guillem Pera, Rosario Tumino, Salvatore Panico, Antonio Agudo, Elio Riboli, Crusius, Jb, Canzian, F, Capellá, G, Peña, A, Pera, G, Sala, N, Agudo, A, Rico, F, Del Giudice, G, Palli, D, Plebani, M, Boeing, H, Bueno de Mesquita, Hb, Carneiro, F, Pala, V, Save, Ve, Vineis, P, Tumino, R, Panico, Salvatore, Berglund, G, Manjer, J, Stenling, R, Hallmans, G, Martínez, C, Dorronsoro, M, Barricarte, A, Navarro, C, Quirós, Jr, Allen, N, Key, Tj, Binghan, S, Caldas, C, Linseisen, J, Kaaks, R, Overvad, K, Tjønneland, A, Büchner, Fc, Peeters, Ph, Numans, Me, Clavel Chapelon, F, Trichopoulou, A, Lund, E, Jenab, M, Rinaldi, S, Ferrari, P, Riboli, E, González, C. A., University of Groningen, Pathology, General practice, and CCA - Disease profiling

Subjects
Male, PROMOTER, Gastroenterology, cytokine genes, Genotype, Medicine, Prospective Studies, Prospective cohort study, Stomach cancer, Lymphotoxin-alpha, POPULATION, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], biology, Hematology, ASSOCIATION, Middle Aged, European Prospective Investigation into Cancer and Nutrition, Europe, Oncology, Cytokines, severe chronic atrophic gastritis, Female, INTERLEUKIN-1 POLYMORPHISMS, Adult, medicine.medical_specialty, CARCINOMA, Nutritional Status, Adenocarcinoma, GASTRIC-CANCER, HELICOBACTER-PYLORI, INTERLEUKIN-1 POLYMORPHISMS, CARCINOMA, POPULATION, METAANALYSIS, ASSOCIATION, INDIVIDUALS, PROMOTER, HELICOBACTER-PYLORI, Stomach Neoplasms, Internal medicine, CagA, Humans, Genetic Predisposition to Disease, ddc:610, gastric carcinoma, METAANALYSIS, Aged, Polymorphism, Genetic, business.industry, Tumor Necrosis Factor-alpha, Interleukins, Case-control study, Odds ratio, Helicobacter pylori, biology.organism_classification, medicine.disease, INDIVIDUALS, Haplotypes, Case-Control Studies, Immunology, business, polymorphisms, CHINESE, GASTRIC-CANCER
Abstract

BACKGROUND: The relative contribution to gastric cancer (GC) risk of variants in genes that determine the inflammatory response remains mostly unknown and results from genotyping studies are inconsistent. PATIENTS AND METHODS: A nested case-control study within the prospective European Prospective Investigation into Cancer and Nutrition cohort was carried out, including 248 gastric adenocarcinomas and 770 matched controls. Twenty common polymorphisms at cytokine genes [interleukin (IL)1A, IL1B, IL1RN, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, lymphotoxin alpha and tumor necrosis factor (TNF)] were analyzed. Antibodies against Helicobacter pylori (Hp) and CagA were measured. RESULTS: IL1RN 2R/2R genotype [odds ratio (OR) 2.43; 95% confidence interval (CI) 1.19-4.96] and allele IL1RN Ex5-35C were associated with an increased risk of Hp(+) non-cardia GC. IL8 -251AA genotype was associated with a decreased risk of Hp(+) non-cardia GC (OR 0.51; 95% CI 0.32-0.81), mainly of the intestinal type. These associations were not modified by CagA status. Carriers of IL1B -580C and TNF -487A alleles did not associate with an increased risk. A moderately increased risk of Hp(+) non-cardia GC for IL4R -29429T variant was observed (OR 1.74; 95% CI 1.15-2.63). CONCLUSION: This prospective study confirms the association of IL1RN polymorphisms with the risk of non-cardia GC and indicates that IL8 -251T>A may modify the risk for GC. Some authors are partners of ECNIS, a network of excellence of the EC (FP6 contract 513943).

Published
2008

19. CDH1 gene polymorphisms, smoking, Helicobacter pylori infection and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST)

Author

Françoise Clavel-Chapelon, Majken K. Jensen, Heiner Boeing, María José Sánchez, Carine Biessy, Roger Stenling, Elio Riboli, Carlos A. González, James D. McKay, Miren Dorronsoro, Nadia Slimani, Petra H.M. Peeters, Paolo Vineis, Núria Sala, Salvador Pena, Pietro Ferrari, Domenico Palli, Manuela M. Bergmann, Anja Olsen, Timothy J. Key, Göran Hallmans, Mazda Jenab, Amalia Mattiello, Kim Overvad, Eva Ardanaz, Jakob Linseisen, José Ramón Quirós, Mattijs E. Numans, Sabina Rinaldi, Marie-Christine Boutron-Ruault, Sheila Bingham, Jonas Manjer, J. B.A. Crusius, Antonia Trichopoulou, Fátima Carneiro, Anne Tjønneland, Gabriel Maria Capella Munar, Theodora Psaltopoulou, Sara Regnér, Rosario Tumino, Stewart Laing, Paolo Boffetta, Christina Georgila, H. Bas Bueno-de-Mesquita, Valeria Pala, Kay-Tee Khaw, Eiliv Lund, Rudolf Kaaks, Carmen Navarro Sánchez, Jenab, M., McKay, J.D., Ferrari, P., Biessy, C., Laing, S., Capella Munar, G.M., Sala, N., Peña, S., Crusius, J.B.A., Overvad, K., Jensen, M.K., Olsen, A., Tjonneland, A., Clavel-Chapelon, F., Boutron-Ruault, M.-C., Kaaks, R., Linseisen, J., Boeing, H., Bergmann, M.M., Trichopoulou, A., Georgila, C., Psaltopoulou, T., Mattiello, A., Vineis, P., Pala, V., Palli, D., Tumino, R., Numans, M.E., Peeters, P.H.M., Bueno-de-Mesquita, H.B., Lund, E., Ardanaz, E., Sánchez, M.-J., Dorronsoro, M., Navarro Sanchez, C., Quirós, J.R., Hallmans, G., Stenling, R., Manjer, J., Régner, S., Key, T., Bingham, S., Khaw, K.-t., Slimani, N., Rinaldi, S., Boffetta, P., Carneiro, F., Riboli, E., Gonzalez, C., General practice, CCA - Disease profiling, and Pathology

Subjects
Male, Cancer Research, medicine.medical_specialty, Genotype, Spirillaceae, Gastroenterology, CDH1, Helicobacter Infections, Antigens, CD, Stomach Neoplasms, Internal medicine, medicine, Humans, E-Cadherin CDH1 Gastric cancer EPIC Smoking Helicobacter pylori Gastric adenocarcinoma, Stomach cancer, Gene, Polymorphism, Genetic, biology, Helicobacter pylori, Smoking, Cancer, Middle Aged, biology.organism_classification, medicine.disease, Cadherins, European Prospective Investigation into Cancer and Nutrition, Europe, Oncology, Immunology, biology.protein, Female, Epidemiologic Methods
Abstract

Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. E-Cadherin is an adhesion molecule that is thought to be involved in GC. Germline mutations in the E-Cadherin gene (CDH1) have been identified in hereditary diffuse GC. Also, a promoter polymorphism at position -160 C/A has been suggested to lead to transcriptional down regulation and has been shown to affect GC risk in some studies. However, very little information exists on the GC risk association of other CDH1 polymorphisms and it is unclear whether any associations may be different by GC anatomical sites or histological types. Thus, a case-control study (cases = 245/controls = 950) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort was conducted to assess the GC risk association of eight CDH1 gene polymorphisms. None of the CDH1 polymorphisms or haplotypes analysed were associated with GC risk and no differences of effect were observed by Helicobacter pylori infection status. However, three CDH1 polymorphisms in the same haplotype block, including the CDH1-160C/A, interacted with smoking to increase GC risk in smokers but not in never smokers. These findings should be confirmed in larger independent studies. © 2008 Elsevier Ltd. All rights reserved.

Published
2008

20. The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition

Author

Kim Overvad, Jonas Manjer, Domenico Palli, José Ramón Quirós, Françoise Clavel-Chapelon, Simone J. P. M. Eussen, Marie-Christine Boutron-Ruault, Rudolf Kaaks, Carmen Navarro, Aurelio Barricarte, Per Magne Ueland, Åse Fredriksen, Klaus Meyer, Guillem Pera, Anne Tjønneland, Valeria Pala, Eiliv Lund, Pietro Ferrari, Rosario Tumino, Carmen Martinez, Timothy J. Key, Frederike L. Büchner, Paolo Vineis, Jakob Linseisen, Carlos A. González, Salvatore Panico, Elio Riboli, Cornelia Weikert, Göran Hallmans, Göran Berglund, Mattijs E. Numans, Mazda Jenab, Fátima Carneiro, Stein Emil Vollset, Giuseppe Del Giudice, Roger Stenling, Antonio Agudo, Jannicke Igland, Naomi E. Allen, Sheila Bingham, Antonia Trichopoulou, H. Bas Bueno-de-Mesquita, Håkon K. Gjessing, Núria Sala, Petra H.M. Peeters, Gabriel Capellá, Heiner Boeing, Miren Dorronsoro, Nadia Slimani, University of Groningen, Vollset, Se, Igland, J, Jenab, M, Fredriksen, A, Meyer, K, Eussen, S, Gjessing, Hk, Ueland, Pm, Pera, G, Sala, N, Agudo, A, Capella, G, Del Giudice, G, Palli, D, Boeing, H, Weikert, C, Bueno de Mesquita, Hb, Carneiro, F, Pala, V, Vineis, P, Tumino, R, Panico, Salvatore, Berglund, G, Manjer, J, Stenling, R, Hallmans, G, Martínez, C, Dorronsoro, M, Barricarte, A, Navarro, C, Quirós, Jr, Allen, N, Key, Tj, Bingham, S, Linseisen, J, Kaaks, R, Overvad, K, Tjønneland, A, Büchner, Fl, Peeters, Ph, Numans, Me, Clavel Chapelon, F, Boutron Ruault, Mc, Trichopoulou, A, Lund, E, Slimani, N, Ferrari, P, Riboli, E, and González, C. A.

Subjects
Male, Epidemiology, Atrophic gastritis, C677T POLYMORPHISM, EPIC-EURGAST, Gastroenterology, Cohort Studies, chemistry.chemical_compound, Risk Factors, Prospective Studies, GENETIC POLYMORPHISMS, Prospective cohort study, Stomach cancer, Homocysteine, biology, Middle Aged, European Prospective Investigation into Cancer and Nutrition, Europe, Vitamin B 12, MICROBIOLOGICAL ASSAY, Oncology, MENDELIAN RANDOMIZATION, Female, Adult, Gastritis, Atrophic, medicine.medical_specialty, Polymorphism, Single Nucleotide, Cobalamin, Folic Acid, Stomach Neoplasms, Interventional oncology [UMCN 1.5], Internal medicine, 10-METHYLENETETRAHYDROFOLATE REDUCTASE, medicine, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Aged, CHINESE POPULATION, business.industry, Cancer, medicine.disease, HELICOBACTER-PYLORI INFECTION, digestive system diseases, Surgery, 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE, STOMACH-CANCER, chemistry, Case-Control Studies, Methylenetetrahydrofolate reductase, biology.protein, MTHFR POLYMORPHISMS, business, Methylmalonic Acid, Blood sampling
Abstract

Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n = 247) and controls (n = 631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P = 0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C→T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A→C polymorphism (odds ratio, 1.47 for CC versus AA; P = 0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2416–24)

Published
2007

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