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Background: Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking. Methods: Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original v. conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings. Results: Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as CHRNA2 , CUL3 , and PCDH7. Conclusions: Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health. [ABSTRACT FROM AUTHOR]

Background: Selenium is an essential trace element with both beneficial and detrimental effects on health depending on dose and chemical form. Currently, there is debate on recommendations for selenium supplementation as a public health measure to improve immune function and reduce infectious disease susceptibility. Objectives: We performed a systematic review and meta-analysis of experimental studies assessing the effect of selenium supplementation on immunity-related outcomes in healthy people. Methods: We undertook a search of published and unpublished studies in literature databases such as PubMed/MEDLINE, Embase, and clinicaltrials.gov up to 17 October, 2022, and performed a meta-analysis comparing the effects on immunity-related outcomes between Se-supplemented versus control arms. Whenever possible we assessed the nonlinear relation using a dose-response approach. Results: 9 trials were included, 5 in North America, and 4 in Europe, with a duration between 8 and 48 weeks and supplementation of both inorganic and organic selenium forms. Selenium supplementation did not substantially affect immunoglobulin or white blood cell concentrations, and the dose-response meta-analysis indicated that an increase in plasma selenium concentrations above 100 µg/L did not further increase IgA levels nor T cells. An inverted U-shaped relation emerged for NK cell count, with a lower number of these cells both below and above 120 µg/L. The only beneficial effect of selenium supplementation was the increased activity for NK lysis, but the available data did not permit dose-response analysis. Cytokine levels were substantially unaffected by selenium supplementation. Conclusions: Although some of the data suggested beneficial effects of selenium supplementation on immune function, the overall picture appears to be inconsistent and heterogeneous due to differences in trial duration and interventions, plus evidence of null and even detrimental effects. Overall, the evidence that we extracted from the literature in this systematic review does not support the need to supplement selenium beyond the recommended dietary intake to obtain beneficial effects on immune function. This trial was registered at PROSPERO (CRD42022312280). [ABSTRACT FROM AUTHOR]

Recently, Elsinoë piri has become an important pathogen in unsprayed and organic apple orchards. The increasing demand for organic apples as well as the limited use of fungicides imposed by European legislation has turned this pathogen, which has been known for over a century in Europe, into a resurgent phytosanitary threat. It also represents a new trait to be taken into account in apple breeding programmes. As E. piri is extremely difficult to isolate and causes symptoms that can be confused with those caused by other pathogens, a quantitative PCR (qPCR) test has been developed based on the internal transcribed spacer (ITS) region of the rDNA gene. This test, which displays a low limit of detection, allows the early detection of the fungus in apple leaves. As a quantitative method, it is a promising tool for breeding purposes as it can be used on leaves to assess the level of quantitative resistance of apple cultivars to the disease. The molecular test is also useful to gain knowledge on the epidemiology of this re‐emerging fungal disease. Spore trapping conducted in 2015, 2016 and 2020 using Rotorod devices and the qPCR test showed that airborne inoculum is released at the end of the growing season. Tests were also carried out to demonstrate that the pathogen was detected in buds during winter. A comparison of 18 E. piri isolates based on the sequencing of five genome regions highlighted a high genotypic diversity. All these isolates were detected with the qPCR test developed in this study. [ABSTRACT FROM AUTHOR]

Simple Summary: Genetic variants explaining approximately 40% of familial breast cancer risk have been identified, thus leaving a significant fraction of the heritability of this disease still unexplained. The exact nature of this missing fraction is unknown; more extensive sequencing efforts could potentially identify new moderate-penetrance breast cancer risk alleles. The aim of this study was to perform a large-scale whole-exome sequencing study, followed by a targeted validation, in breast cancer patients and healthy women of European descent. We identified 20 novel genes with modest evidence of association (p-value < 0.05) for either overall or subtype-specific breast cancer; however, much larger studies are needed to confirm the exact role of these genes in susceptibility to breast cancer. Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes. [ABSTRACT FROM AUTHOR]

Aim: We assessed real-world patient demographics and BRCA1/2 mutation testing rates among adult women with HER2-negative advanced breast cancer (ABC). Methods: Oncologists across the USA and in France, Germany, Italy, Spain and the UK provided medical chart data in 2015 and 2017. Results: Overall, 28% of patients received BRCA1/2 mutation testing. Untested patients were more likely to be aged ≥45 years, have hormone receptor-positive/HER2-negative ABC and have no known family history of breast/ovarian cancer. BRCA1/2 mutation testing rates were significantly lower in the European countries, women aged ≥45 years, women without a known family history of breast/ovarian cancer, and women with hormone receptor-positive/HER2-negative ABC versus advanced triple-negative breast cancer. Conclusion:BRCA1/2 mutation testing rates were low, and disparities were observed in patient characteristics among BRCA1/2 mutation-tested versus untested patients. [ABSTRACT FROM AUTHOR]

Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 case subjects and 279,507 control subjects from 7 European-ancestry cohorts, including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five variants had minor allele frequency of <5% and were each associated with more than a doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19; P = 1 × 10-16) and a stronger effect in men than in women (for interaction, P = 7 × 10-7). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL cholesterol and a 20% increase in triglycerides; colocalization analysis linked this signal to reduced expression of the nearby PELO gene. These results demonstrate that recessive models, when compared with GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes. [ABSTRACT FROM AUTHOR]

The aims of this centre-based survey, promoted and disseminated by the European Heart Rhythm Association (EHRA) was to investigate the current practice for the investigation of Sudden Unexplained Death in the Young (SUDY) amongst European countries. An online questionnaire composed of 21 questions was submitted to the EHRA Research Network, European Cardiac Arrhythmia Genetics (ECGen) Focus Group members, and European Reference Network GUARD-Heart healthcare partners. There were 81 respondents from 24 European countries. The majority (78%) worked in a dedicated clinic focusing on families with inherited cardiac conditions and/or SUDY or had easy access to a nearby one. On average, an autopsy was performed in 43% of SUDY cases. Macroscopic examination of the body and all organs were completed in 71% of cases undergoing autopsy, and expert cardiac examination in 32%. Post-mortem genetic testing was requested on average in 37% of Sudden Arrhythmic Death Syndrome (SADS) cases, but not at all by 20% of survey respondents. Psychological support and bereavement counselling for SADS/SUDY families were available for ≤50% of participants. Whilst electrocardiogram (ECG) and echocardiography were largely employed to investigate SADS relatives, there was an inconsistent approach to the use of provocative testing with exercise ECG, sodium channel blocking drugs, and/or epinephrine and genetic testing. The survey highlighted a significant heterogeneity of service provision and variable adherence to current recommendations for the investigation of SUDY, partly attributable to the availability of dedicated units and specialist tests, genetic evaluation, and post-mortem examination. [ABSTRACT FROM AUTHOR]

Aims: Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information has not been presented, and the extent to which a normal body weight can offset a high lifetime genetic risk is unknown. Methods: We used data from 15,671 diabetes‐free participants of European ancestry aged 45 years and older from the prospective population‐based ARIC study and Rotterdam Study (RS). We quantified the remaining lifetime risk of diabetes stratified by genetic risk and quantified the effect of normal weight in terms of relative and lifetime risks in low, intermediate and high genetic risk. Results: At age 45 years, the lifetime risk of type 2 diabetes in ARIC in the low, intermediate and high genetic risk category was 33.2%, 41.3% and 47.2%, and in RS 22.8%, 30.6% and 35.5% respectively. The absolute lifetime risk for individuals with normal weight compared to individuals with obesity was 24% lower in ARIC and 8.6% lower in RS in the low genetic risk group, 36.3% lower in ARIC and 31.3% lower in RS in the intermediate genetic risk group, and 25.0% lower in ARIC and 29.4% lower in RS in the high genetic risk group. Conclusions: Genetic variants for type 2 diabetes have value in estimating the lifetime risk of type 2 diabetes. Normal weight mitigates partly the deleterious effect of high genetic risk. [ABSTRACT FROM AUTHOR]

Sweden has since the start of the pandemic a COVID-19 mortality rate that is 4 to 10 times higher than in the other Nordic countries. Also, measured as age-standardized all-cause excess mortality in the first half of 2020 compared to previous years Sweden failed in comparison with the other Nordic countries, but only among the elderly. Sweden has large socioeconomic and ethnic inequalities in COVID-19 mortality. Geographical, ethnic, and socioeconomic inequalities in mortality can be due to differential exposure to the virus, differential immunity, and differential survival. Most of the country differences are due to differential exposure, but the socioeconomic disparities are mainly driven by differential survival due to an unequal burden of comorbidity. Sweden suffered from an unfortunate timing of tourists returning from virus hotspots in the Alps and Sweden's government response came later and was much more limited than elsewhere. The government had an explicit priority to protect the elderly in nursing and care homes but failed to do so. The staff in elderly care are less qualified and have harder working conditions in Sweden, and they lacked adequate care for the clients. Sweden has in recent years diverged from the Scandinavian welfare model by strong commercialization of primary care and elderly care. [ABSTRACT FROM AUTHOR]

Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.Funding: British Heart Foundation. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is a vasculitis of unknown origin of small and medium caliber blood vessels, especially involving coronary arteries and is the leading cause of acquired heart disease in childhood in developed countries. Although rarely, it can recur: most recurrences occur within 2 years of the initial episode. No data are available on incidence of recurrent KD in Europe and multiple recurrences are rarely seen. We reviewed the medical literature on Kawasaki disease recurrence and reported a new case of Kawasaki disease recurrence in a child with SARS-CoV-2 infection. We believe that in our case SARS Cov2 acted as a trigger capable to determine, in a genetically susceptible individual, a second recurrence of the disease. In the Covid-19 era we affirm the importance for Kawasaki disease to be tested for SARS Cov2 infection. [ABSTRACT FROM AUTHOR]

Importance: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear.Objectives: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system.Design, Setting, and Participants: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020.Main Outcomes and Measures: Accuracy and generalizability of prognostic systems.Results: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results.Conclusions and Relevance: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation. [ABSTRACT FROM AUTHOR]

Context: Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure.Objective: To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms.Design: Cross-sectional study.Setting: University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT).Patients: We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs).Intervention: Ribonucleic acid (RNA) sequencing.Main Outcome Measures: Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing.Results: Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation.Conclusions: MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors. [ABSTRACT FROM AUTHOR]

Atypical haemolytic uraemic syndrome is an ultra-rare, life-threatening disease. Causative variants in genes that encode complement factors can be identified in 40–70% of cases. We performed genetic analysis of 21 Czech children with atypical haemolytic uraemic syndrome. Genetic or acquired predisposition to the disease was identified in the majority of our patients: CFHR1 and CFHR3 deletions in 14/21 (67%; 13 of them were positive for anti-complement factor H antibodies), variants in complement genes or DGKE in 13/21 (62%). Multiple genetic findings were identified in eight patients (38%). The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population was estimated to be 0.092 (CI 0.053–0.131) cases per million inhabitants and 0.92 (CI 0.53–1.32) cases per 100,000 births for the entire reporting period. Ten patients were initially treated with plasma exchange and eight with eculizumab or with a combination of eculizumab and plasma exchange. At the last follow-up, 20 patients were alive and one patient had end-stage renal disease. Conclusion: The incidence of atypical haemolytic uraemic syndrome in the Czech paediatric population corresponds to the reported incidence in Europe. We detected the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies in Czech paediatric patients. Treatment by eculizumab led to superior outcomes and prevention of the disease relapses compared with plasma exchange therapy. Our results may help to understand the polygenic nature of atypical haemolytic uraemic syndrome as a disease that results from a combination of various risk factors. What is Known: • Atypical haemolytic uraemic syndrome (aHUS) is considered a polygenic and multifactorial disease. Genetic predisposition to aHUS is identified in 40–70% of children. • Anti-complement factor H antibodies are usually found in 6–25% of affected children. What is New: • Potentially causative genetic or acquired factors were confirmed in the majority of patients. The prevailing finding was the unusually high rate of CFHR1/CFHR3 deletions associated with anti-complement factor H antibodies (62% of patients). • The incidence of aHUS in Czech children is 0.092 (CI 0.053–0.131) cases per million inhabitants and 0.92 (CI 0.53–1.32) cases per 100,000 births for the entire reporting period. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans.Methods and Results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351).Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS. [ABSTRACT FROM AUTHOR]

Objective: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. TRIM63 has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in TRIM63 and the development of HCM.Methods: TRIM63 was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls.Results: Sixteen index cases with rare homozygous or compound heterozygous variants in TRIM63 (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%).Conclusion: TRIM63 appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction. [ABSTRACT FROM AUTHOR]

Background: Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions.Methods: Analyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions.Results: Noteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth.Conclusions: Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a common disorder that affects 6-10% of reproductive age women. In a previous study, we demonstrated that a polymorphism in let-7 microRNA-binding site in the 3' untranslated region of the KRAS gene was found in 31% of subjects with endometriosis resistant to medical therapy. This polymorphism was now tested in a large, case-control study.Methods: Peripheral blood or peritoneal biopsies from 2,077 European subjects with or without endometriosis and known infertility were tested for the presence of the variant allele using polymerase chain reaction.Results: Histologically proven endometriosis was found in 1,140 subjects, while 937 subjects were disease free. Variant allele carrier rates in subjects with and without endometriosis were 15.7 and 15.1%, respectively. No association between the variant KRAS allele and stage of the disease, age at surgery, body mass index, or type of infertility was identified.Conclusion: A germ-line single-nucleotide polymorphism in the let-7 microRNA-binding site of the KRAS gene was not associated with sporadic endometriosis in an infertile Caucasian population in this large case-control study. However, it remains possible that this gene variant may be a marker of treatment resistance. Further studies on the role of this polymorphism in endometriosis are needed. [ABSTRACT FROM AUTHOR]

The aim of this study was to conduct a prospective analysis of the association between negative life events (NLEs) and respiratory infections in children genetically at risk for islet autoimmunity (IA) and type 1 diabetes (T1D). Long‐ and short‐term temporal associations between NLEs and rate of respiratory infection episodes (RIEs) in 5,618 children in The Environmental Determinants of Diabetes in the Young study for at least 1 up to 4 years were analysed. All models were adjusted for demographic, day care, season of infection, and psychosocial factors associated with the rate of child RIEs between study visits. The rate of child RIEs was 26% higher in Europe (Sweden, Finland, Germany) than in the United States (rate ratio [RR] = 1.26, p < 0.001). However, the percentage of child NLEs (odds ratio [OR] = 1.18, p < 0.001) and mother NLEs (OR = 1.83, p < 0.001) was higher in the United States compared with Europe. In both continents (Europe, RR = 1.12, p < 0.001; United States, RR = 1.07, p = 0.006), high child cumulative NLEs (>1 NLE per year since study inception) was significantly associated with an increased rate of child RIEs. This large‐scale prospective study confirms observations that stress may increase the susceptibility for infections in paediatric populations and suggests at least one mechanism by which stress could increase risk for IA and T1D in genetically at risk children. [ABSTRACT FROM AUTHOR]

Background African Americans (AAs) and Hispanic/Latinos (HLs) have higher risk of obesity than European Americans, possibly due to differences in environment and lifestyle, but also reflecting differences in genetic background. Objective To gain insight into factors contributing to BMI (in kg/m2) and obesity risk (BMI ≥ 30) among ancestry groups, we investigate the role of self-reported ancestry, proportion of genetic African ancestry, and country of birth in 6368 self-identified AA and 7569 HL participants of the New York–based Bio Me Biobank. Methods AAs and HLs are admixed populations that trace their genetic ancestry to the Americas, Africa, and Europe. The proportion of African ancestry (PAA), quantified using ADMIXTURE, was higher among self-reported AA (median: 87%; IQR: 79–92%) than among HL (26%; 15–41%) participants. Approximately 18% of AA and 59% of HL participants were non–US-born. Results Because of significant differences between sexes (P PAA*sex interaction = 4.8 × 10−22), we considered women and men separately. Among women, country of birth and genetic ancestry contributed independently to BMI. US-born women had a BMI 1.99 higher than those born abroad (P  = 7.7 × 10−25). Every 10% increase in PAA was associated with a BMI 0.29 higher (P  = 7.1 × 10−10). After accounting for PAA and country of birth, the contribution of self-reported ancestry was small (P  = 0.046). The contribution of PAA to higher BMI was significantly more pronounced among US-born (0.35/10%PAA, P  = 0.003) than among non–US-born (0.26/10%PAA, P  = 0.01) women (P PAA*sex interaction = 0.004). In contrast, among men, only US-born status influenced BMI. US-born men had a BMI 1.33 higher than non–US-born men, whereas PAA and self-reported ancestry were not associated with BMI. Associations with obesity risk were similar to those observed for BMI. Conclusions Being US-born is associated with a substantially higher BMI and risk of obesity in both men and women. Genetic ancestry, but not self-reported ancestry, is associated with obesity susceptibility, but only among US-born women in this New York–based population. [ABSTRACT FROM AUTHOR]

Background: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence.Objective: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries.Methods: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association.Results: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea.Conclusions: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses. [ABSTRACT FROM AUTHOR]

Introduction: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown.Methods: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status.Results: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10-6; CYP2A7, p = 7.50 × 10-5; CYP2B6, p = 4.04 × 10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (β = 0.11, p = 5.58 × 10-4) and controls (β = 0.12, p = 3.86 × 10-5) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10-4).Conclusions: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls.Implications: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker. [ABSTRACT FROM AUTHOR]

Background: Plazomicin is a next-generation aminoglycoside that was developed to overcome common aminoglycoside-resistance mechanisms.Objectives: We evaluated the activity of plazomicin and comparators against clinical isolates collected from 26 European and adjacent countries during 2014 and 2015 as part of the Antimicrobial Longitudinal Evaluation and Resistance Trends (ALERT) global surveillance programme.Methods: All 4680 isolates collected from 45 hospitals were tested for susceptibility to antimicrobials using the reference broth microdilution method. Selected isolates were screened for genes encoding carbapenemases, aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methyltransferases.Results: Plazomicin (MIC50/90 0.5/2 mg/L) inhibited 95.8% of Enterobacteriaceae at ≤2 mg/L, including carbapenem-resistant Enterobacteriaceae (MIC50/90 0.25/128 mg/L). Plazomicin was more active compared with other aminoglycosides against isolates carrying blaKPC (MIC50/90 0.25/2 mg/L), isolates carrying blaOXA-48-like (MIC50/90 0.25/16 mg/L) and carbapenemase-negative isolates (MIC50/90 0.25/1 mg/L). Approximately 60% of the isolates harbouring blaVIM and blaNDM-1 carried 16S rRNA methyltransferases (mainly rmtB and armA). AME genes were detected among 728 isolates and 99.0% of these were inhibited by plazomicin at ≤2 mg/L. Plazomicin activity against Pseudomonas aeruginosa (MIC50/90 4/8 mg/L) was similar to amikacin activity (MIC50/90 2/16 mg/L). Plazomicin demonstrated activity against CoNS (MIC50/90 0.12/0.25 mg/L) and Staphylococcus aureus (MIC50/90 0.5/1 mg/L). Plazomicin activity was limited against Acinetobacter spp. (MIC50/90 8/>128 mg/L), Enterococcus spp. (MIC50/90 32/128 mg/L) and Streptococcus pneumoniae (MIC50/90 32/64 mg/L).Conclusions: Plazomicin demonstrated activity against Enterobacteriaceae isolates tested in this study, including isolates carrying AMEs and a high percentage of the carbapenem-non-susceptible isolates. Plazomicin displayed activity against staphylococci. [ABSTRACT FROM AUTHOR]

The disturbances of the 11p15.5 chromosomal region are associated with Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Wilms tumor, IMAGe syndrome, and idiopathic hemihyperplasia. The aim of this research was to examine the hypothesis that 11p15.5 initially became unstable in the European population about 200 years ago. The medical literature from 1557 onwards, especially treatises on teratology, body asymmetry, and books of normal and pathologic anatomy, was searched for any mentioning of lateral body asymmetry, macroglossia and other possible visually detectable symptoms associated with the above-mentioned syndromes. The results indicate that lateral body asymmetry was not described before the first half of the 19th century, it was mentioned in the 1820s, and the first description of a true case was published in 1850. All first cases of hemihyperplasia were reported in continental Europe. Historical data suggest that the 11p15.5 chromosomal region became unstable in the first half of the 19th century. Our preliminary hypothesis is that de novo mutation occurred in continental Europe. Additional genetic research is needed to investigate the development of 11p15.5 instability during this period. [ABSTRACT FROM AUTHOR]

Background: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.Methods: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.Findings: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.Interpretation: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund). [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival.Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. [ABSTRACT FROM AUTHOR]

Objective: To investigate fertility outcome in individuals with different forms of disorders of sex development (DSD), if assisted reproductive technology (ART) was used, and the patients' satisfaction with the information they had received.Design: A cross-sectional multicenter study, dsd-LIFE.Setting: Not applicable.Patient(s): A total of 1,040 patients aged ≥16 years with different DSD diagnoses participated.Intervention(s): A web-based questionnaire was filled out by all participants. The participants could chose to take part in somatic investigations including ultrasonography.Main Outcome Measure(s): Information on partner, number of children, ART, adoption and step-children, general health, presence of gonads and uterus, current education and economic situation, received information on fertility issues, and satisfaction with the information, was collected.Result(s): In the total cohort, mean age 32 years, 33% lived with a partner, but only 14% reported having at least one child including 7% with ART, 4% adopted. Only 3.5% of the total cohort had been able to reproduce without ART, most frequently women with congenital adrenal hyperplasia, and only 0.7% of participants with other diagnoses. Of the participants, 72% had received information on fertility, but 17% were not satisfied with the information.Conclusion(s): Fertility outcome is significantly reduced in all types of DSD; however, fertility potential should be assessed individually. The satisfaction with how fertility problems have been discussed can be improved. The care of patients with DSD is complex, should be individualized, and new treatment possibilities incorporated. A close collaboration in multidisciplinary teams is therefore essential to improve the situation for individuals with DSD. [ABSTRACT FROM AUTHOR]

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation. [ABSTRACT FROM AUTHOR]

Background: Current adult celiac disease diagnosis requires histological confirmation. However, pediatric guidelines have proposed biopsy-sparing algorithms.Aims: To explore the applicability of the ESPGHAN criteria and assess the accuracy of serology in predicting disease in adults.Methods: We evaluated 234 consecutive adults showing elevated anti-tTG titers, EMA-positivity, and genetic susceptibility. Patients underwent upper endoscopy with duodenal biopsy. We determined optimal anti-tTG cutoff levels using ROC curves.Results: Mean anti-tTG levels were 71.1 ± 66.5 U/ml; mean normalized levels were 14.8 ± 14.1 × ULN (mean ± SD). Partial/total villous atrophy was present in 36%/55% of cases, respectively. Anti-tTG levels correlated with histology (r s = 0.397, p < 0.001). AUC was similar before and after normalization (0.803 vs 0.807). Applying the ESPGHAN criterion (≥10 × ULN), we calculated a 97.66% PPV. ROC curve analysis showed an optimal cutoff of ≥16 × ULN, with a PPV of 98.86%. Eleven different assays were used for anti-tTG titer determination: Two were prevalent, labeled A (n = 141) and B (n = 59). They performed differently regarding disease prediction (AUC = 0.689 vs 0.925, p < 0.01), showing distinct optimal cutoff values (14.3 × ULN vs 3.7 × ULN), even after standardization (-0.14 vs -1.2).Conclusion: In adult symptomatic patients showing EMA-positivity and genetic susceptibility, anti-tTG titers correlated with histology. ESPGHAN criteria performed similarly to previous studies. However, a calculated 16 × ULN cutoff showed an improved PPV. Among prevalent assays, PPV peaked differently both after normalization and standardization, indicating intrinsic differences in performance, thus preventing uniform prediction of disease in a real-life setting. Assay-specific optimal cutoffs seem possible, but would complicate diagnostic criteria. However, biopsy-sparing strategies in adults could prove useful in challenging patients. [ABSTRACT FROM AUTHOR]

Background/objectives: Milk provides protein and micronutrients, and is recommended by some dietary guidelines, particularly for bone health. Meta-analysis of small randomized controlled trials suggests that milk may increase bone mineral density, but they are very heterogeneous. No randomized controlled trial has assessed the effects of milk on major chronic diseases. Previous Mendelian randomization studies of milk did not consider bone health, found no effects on ischemic heart disease (IHD) or type 2 diabetes (T2D) but higher body mass index. Using larger genetic studies, we estimated the effects of milk on osteoporosis, IHD, T2D, adiposity, lipids and glycemic traits.Subjects/methods: Instrumental variable analysis based on a genetic variant endowing lactase persistence (rs4988235 (MCM6)) was used to obtain estimates for osteoporosis (GEFOS), IHD (CARDIoGRAMplusC4D), T2D (DIAGRAM), adiposity (GIANT), lipids (GLGC) and glycaemic traits (MAGIC). Eye color was a negative control for IHD, as it mirrors the distribution of lactase persistence and IHD in Western Europe.Results: Genetically predicted adult milk consumption was not clearly associated with bone mineral density, IHD (odds ratio (OR): 1.03 per s.d., 95% confidence interval (CI): 0.95-1.12) and or T2D (OR: 0.92, 95% CI: 0.83-1.02) but was associated with higher log-transformed fasting insulin (0.05, 95% CI: 0.02-0.07) and body mass index (0.06, 95% CI: 0.03-0.09). Genetically predicted eye color was not associated with IHD.Conclusions: The lack of association of genetically predicted milk consumption with bone health, IHD or T2D suggests few beneficial effects but is more consistent with milk promoting adiposity. [ABSTRACT FROM AUTHOR]

The association between ALOX5AP SG13S114 polymorphism and ischemic stroke (IS) susceptibility has extensively been investigated, especially in white populations; however, the results were inconclusive. Here, we perform a meta-analysis to clarify the effect of SG13S114 variant on the IS risk in Europeans. The Web of Science, PubMed, EMBASE, and Medline were searched up to August 1st, 2016. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model. In total, 8 case control studies involved 8062 subjects were finally included in this meta-analysis. We observed a significantly decreased IS risk in persons carrying an A allele at the SG13S114 polymorphism compared with those with a T allele (A vs T, OR = 0.856, 95% CI = 0.797-0.919, p < 0.001). In addition, the results of sensitivity and cumulative meta-analysis indicated the robustness of our results. In addition, the publication bias was not detected using the funnel plot and Egger's tests. In summary, the present meta-analysis suggested that the A allele at the ALOX5AP SG13S114 polymorphism is a protective factor for the IS in the Europeans. In addition, further studies with large sample size are needed to validate the association, as well as in other ethnic groups. [ABSTRACT FROM AUTHOR]

Background Genetic differences in the target proteins, metabolizing enzymes and transporters that contribute to inter-individual differences in drug response are not integrated in contemporary drug development programs. Ayurveda, that has propelled many drug discovery programs albeit for the search of new chemical entities incorporates inter-individual variability “ Prakriti ” in development and administration of drug in an individualized manner. Prakriti of an individual largely determines responsiveness to external environment including drugs as well as susceptibility to diseases. Prakriti has also been shown to have molecular and genomic correlates. We highlight how integration of Prakriti concepts can augment the efficiency of drug discovery and development programs through a unique initiative of Ayurgenomics TRISUTRA consortium. Methods Five aspects that have been carried out are (1) analysis of variability in FDA approved pharmacogenomics genes/SNPs in exomes of 72 healthy individuals including predominant Prakriti types and matched controls from a North Indian Indo-European cohort (2) establishment of a consortium network and development of five genetically homogeneous cohorts from diverse ethnic and geo-climatic background (3) identification of parameters and development of uniform standard protocols for objective assessment of Prakriti types (4) development of protocols for Prakriti evaluation and its application in more than 7500 individuals in the five cohorts (5) Development of data and sample repository and integrative omics pipelines for identification of genomic correlates. Results Highlight of the study are (1) Exome sequencing revealed significant differences between Prakriti types in 28 SNPs of 11 FDA approved genes of pharmacogenomics relevance viz. CYP2C19, CYP2B6, ESR1, F2, PGR, HLA-B, HLA-DQA1, HLA-DRB1, LDLR, CFTR, CPS1. These variations are polymorphic in diverse Indian and world populations included in 1000 genomes project. (2) Based on the phenotypic attributes of Prakriti we identified anthropometry for anatomical features, biophysical parameters for skin types, HRV for autonomic function tests, spirometry for vital capacity and gustometry for taste thresholds as objective parameters. (3) Comparison of Prakriti phenotypes across different ethnic, age and gender groups led to identification of invariant features as well as some that require weighted considerations across the cohorts. Conclusion Considering the molecular and genomics differences underlying Prakriti and relevance in disease pharmacogenomics studies, this novel integrative platform would help in identification of differently susceptible and drug responsive population. Additionally, integrated analysis of phenomic and genomic variations would not only allow identification of clinical and genomic markers of Prakriti for application in personalized medicine but also its integration in drug discovery and development programs. [ABSTRACT FROM AUTHOR]

Background: The associations between rs6887695 and 3′-untranslated region (3′-UTR) single-nucleotide polymorphisms (SNPs) withininterleukin-12B(IL-12B) and autoimmune diseases (ADs) remain controversial and inconclusive. The aim of this study was to evaluate the association betweenIL-12B(3′-UTR A/C and rs6887695 C/G SNPs) and ADs by meta-analysis.Methods: PubMed and EMBASE were exhaustively searched for studies on the association betweenIL-12BSNPs and ADs. Publication bias was examined by a funnel plot and Egger’s test. The robustness of the pooled results was assessed by sensitivity analysis. A fixed- or a random-effects model was applied to calculate the pooled odds ratios (ORs).Results: A total of 34 studies were included in this meta-analysis. The pooled results demonstrated thatIL-12Brs6887695 SNPs were significantly associated with the risk of ADs. However, there was no significant association betweenIL-12B3′-UTR SNPs and ADs. When the studies were stratified by ethnicity, significant association betweenIL-12B3′-UTR SNPs and ADs was observed in both Asian and European population. In addition, allele A within 3′-UTR ofIL-12Bgene was found to be a protective factor for T1DM, but a risk factor for psoriasis.Conclusion:TheIL-12B3′-UTR and rs6887695 SNPs are associated with susceptibility to ADs. [ABSTRACT FROM PUBLISHER]

Background: Functional deficiency of mannose-binding lectin (MBL) may contribute to the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that specific MBL2 gene polymorphisms and circulating MBL protein levels are associated with clinically relevant outcomes in the Predicting Outcome using systemic Markers In Severe Exacerbations of COPD PROMISE-COPD cohort.Methods: We followed 277 patients with stable COPD GOLD stage II-IV COPD over a median period of 733 days (IQR 641-767) taking survival as the primary outcome parameter. Patients were dichotomized as frequent (≥ 2 AECOPD/year) or infrequent exacerbators. Serum MBL levels and single nucleotide polymorphisms of the MBL2 gene were assessed at baseline.Results: The MBL2-HYPD haplotype was significantly more prevalent in frequent exacerbators (OR: 3.33; 95% CI, 1.24-7.14, p = 0.01). The median serum MBL concentration was similar in frequent (607 ng/ml, [IQR; 363.0-896.0 ng/ml]) and infrequent exacerbators (615 ng/ml, [IQR; 371.0-942.0 ng/ml]). Serum MBL was not associated with lung function characteristics or bacterial colonization in sputum. However, high serum MBL at stable state was associated with better survival compared to low MBL (p = 0.046, log rank test).Conclusions: In COPD, the HYPD haplotype of MBL2 gene is associated with frequent exacerbations and high serum MBL is linked to increased survival. The PROMISE-COPD study was registered at www.controlled-trials.com under the identifier ISRCTN99586989. [ABSTRACT FROM AUTHOR]

Rationale: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.Objectives: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.Methods: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.Measurements and Main Results: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.Conclusions: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics. [ABSTRACT FROM AUTHOR]

Background. Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, ormortality from, sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. Methods. We genotyped and analyzed 4 important MBL2 single nucleotide polymorphisms (SNPs; rs5030737, rs1800450, rs1800451, and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the United Kingdom. We analyzed the following predefined subgroups and outcomes: 28- day and 6month mortality fromsepsis due to CAP or peritonitis combined, 28-daymortality fromCAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the United Kingdom. Results. There were no significant associations (all P-values were greater than .05 after correction formultiple testing) between MBL2 genotypes and any of our predefined analyses. Conclusions. In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified. [ABSTRACT FROM AUTHOR]

Background Loss-of-function mutations in the filaggrin gene ( FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility. Objectives To investigate the association of the FLG genotype and cancer types in four population-based cohorts. Methods A total of 13 376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses. Results There were 1339 incident cancers (median follow-up 11·4 years). The hazard ratios ( HRs) and 95% confidence intervals ( CIs) for FLG mutation carriers vs. wild types were: for any cancer ( HR 0·95, 95% CI 0·78-1·16), any cancer excluding nonmelanoma skin cancer ( NMSC) ( HR 1·05, 95% CI 0·84-1·31), head and neck cancer ( HR 1·72, 95% CI 0·71-4·15), colorectal cancer ( HR 0·82, 95% CI 0·44-1·52), bronchus and lung cancer ( HR 1·34, 95% CI 0·77-2·33), breast cancer ( HR 0·58, 95% CI 0·30-1·14), uterine cancer ( HR 0·42, 95% CI 0·06-3·10), prostate cancer ( HR 1·09, 95% CI 0·61-1·94), urinary cancer ( HR 1·30, 95% CI 0·51-3·29), malignant melanoma ( HR 1·03, 95% CI 0·41-2·58) and NMSC ( HR 0·70, 95% CI 0·47-1·05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers. Conclusions The only significant associations between FLG loss-of-function mutations and cancer were in subgroup analyses. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by infection with Mycobacterium bovis (M. bovis) and other closely related members of the M. tuberculosis complex (MTC) infects many domestic and wildlife species across Europe. Transmission from wildlife species to cattle complicates the control of disease in cattle. By determining the level of TB hazard for which a given wildlife species is responsible, the potential for transmission to the cattle population can be evaluated. We undertook a quantitative review of TB hazard across Europe on a country-by-country basis for cattle and five widely-distributed wildlife species. Cattle posed the greatest current and potential TB hazard other cattle for the majority of countries in Europe. Wild boar posed the greatest hazard of all the wildlife species, indicating that wild boar have the greatest ability to transmit the disease to cattle. The most common host systems for TB hazards in Europe are the cattle-deerwild boar ones. The cattle-roe deer-wild boar system is found in 10 countries, and the cattle-red deer- wild boar system is found in five countries. The dominance of cattle with respect to the hazards in many regions confirms that intensive surveillance of cattle for TB should play an important role in any TB control programme. The significant contribution that wildlife can make to the TB hazard to cattle is also of concern, given current population and distribution increases of some susceptible wildlife species, especially wild boar and deer, and the paucity of wildlife TB surveillance programmes. [ABSTRACT FROM AUTHOR]

Health-care workers (HCWs) are at increased risk for acquisition of vaccine-preventable diseases (VPDs) and vaccination is justified in order to protect them from occupational exposure and to prevent the spread of VPDs that pose a threat to susceptible patients. Review of European vaccination policies for HCWs revealed significant differences between countries in terms of recommended vaccines, implementation frame (mandatory or recommendation), target HCW groups and health-care settings. Further, the few published studies available identified indicate significant immunity gaps among HCWs against VPDs in Europe. In order to achieve higher vaccination coverage against VPDs stronger recommendations are needed. The issue of mandatory vaccination should be considered for diseases that can be transmitted to susceptible patients (influenza, measles, mumps, rubella, hepatitis B, pertussis, varicella). The acceptance of vaccinations and of mandatory vaccinations by HCWs is a challenge and appears to be VPD-specific. [ABSTRACT FROM AUTHOR]

We analyzed the species distribution of Candida blood isolates ( CBIs), prospectively collected between 2004 and 2009 within FUNGINOS, and compared their antifungal susceptibility according to clinical breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing ( EUCAST) in 2013, and the Clinical and Laboratory Standards Institute ( CLSI) in 2008 (old CLSI breakpoints) and 2012 (new CLSI breakpoints). CBIs were tested for susceptiblity to fluconazole, voriconazole and caspofungin by microtitre broth dilution (Sensititre® YeastOne™ test panel). Of 1090 CBIs, 675 (61.9%) were C. albicans, 191 (17.5%) C. glabrata, 64 (5.9%) C. tropicalis, 59 (5.4%) C. parapsilosis, 33 (3%) C. dubliniensis, 22 (2%) C. krusei and 46 (4.2%) rare Candida species. Independently of the breakpoints applied, C. albicans was almost uniformly (>98%) susceptible to all three antifungal agents. In contrast, the proportions of fluconazole- and voriconazole-susceptible C. tropicalis and F-susceptible C. parapsilosis were lower according to EUCAST/new CLSI breakpoints than to the old CLSI breakpoints. For caspofungin, non-susceptibility occurred mainly in C. krusei (63.3%) and C. glabrata (9.4%). Nine isolates (five C. tropicalis, three C. albicans and one C. parapsilosis) were cross-resistant to azoles according to EUCAST breakpoints, compared with three isolates (two C. albicans and one C. tropicalis) according to new and two (2 C. albicans) according to old CLSI breakpoints. Four species ( C. albicans, C. glabrata, C. tropicalis and C. parapsilosis) represented >90% of all CBIs. In vitro resistance to fluconazole, voriconazole and caspofungin was rare among C. albicans, but an increase of non-susceptibile isolates was observed among C. tropicalis/ C. parapsilosis for the azoles and C. glabrata/ C. krusei for caspofungin according to EUCAST and new CLSI breakpoints compared with old CLSI breakpoints. [ABSTRACT FROM AUTHOR]

Methods for susceptibility testing of Aspergillus are developed and validated by the European Committee on Antibiotic Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing. Breakpoints for phenotypic antimicrobial susceptibility testing have been determined by breakpoint committees and as part of regulatory processes for the approval of new drugs. Dosages, pharmacokinetics, resistance mechanisms, MIC distributions, pharmacodynamics and epidemiological cut-off values are used in the breakpoint-setting process. Clinical breakpoints are for everyday use in the clinical laboratory to advise on patient therapy. Resistance in Aspergillus fumigatus has been increasingly reported since standards became available. [ABSTRACT FROM AUTHOR]

Complex multifactorial disorders usually arise in individuals genetically at risk in the presence of permissive environmental factors. For many of these diseases, predisposing gene variants are partly known while the identification of the environmental component is much more difficult. This study aims to investigate whether there are correlations between the incidence of two complex traits, multiple sclerosis and type 1 diabetes, and some chemical elements and compounds present in soils and stream sediments in Europe. Data were obtained from the published literature and analyzed by calculating the mean values of each element and of disease incidence for each Country, respectively, 17 for multiple sclerosis and 21 for type 1 diabetes. Correlation matrices and regression analyses were used in order to compare incidence data and geochemical data. R correlation index and significance were evaluated. The analyses performed in this study have revealed significant positive correlations between barium and sodium oxide on one hand and multiple sclerosis and diabetes incidences on the other hand that may suggest interactions to be evaluated between silicon-rich lithologies and/or marine environments. The negative correlations shown by cobalt, chromium and nickel (typical of silicon-poor environment), which in this case can be interpreted as protective effects against the two diseases onset, make the split between favorable and protective environments even more obvious. In conclusion, if other studies will confirm the involvement of the above elements and compounds in the etiology of these pathologies, then it will be possible to plan strategies to reduce the spread of these serious pandemics. [ABSTRACT FROM AUTHOR]

Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02×10-06, OR=1.90), stenosing (p=3.16×10-06, OR=1.82) and penetrating (p=1.26×10-02, OR=1.25) CD behaviours, and need for surgery (p=2.28×e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86×10-06, OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48×10-06, OR=0.35) and surgical rate (p=1.71×10-07, OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12×10-03, HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01×10-02, HR=1.29) among patients with low and high score. Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to explore whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to ovarian cancer. Methods: Meta-analyses were conducted on the associations between the VDR FokI, BsmI, ApaI, and TaqI polymorphisms and ovarian cancer. Results: A total of 12 comparison studies were considered in the meta-analysis, which involved 3716 patients and 5059 controls. Meta-analysis of the VDR FokI polymorphism showed an association between ovarian cancer and the f allele in European populations (OR = 1.094, 95% CI = 1.028-1.163, p = 0.004). Meta-analysis revealed an association between ovarian cancer and the ApaI A allele in all study subjects and Europeans as a sub-group (OR = 1.235, 95% CI = 1.019-1.497, p = 0.032 and OR = 1.287, 95% CI = 1.029-1.609, p = 0.027, respectively). No association was found between ovarian cancer and the BsmI and Taq polymorphisms (OR for B allele = 1.084, 95% CI = 0.936-1.255, p = 0.280, OR for the T allele = OR = 0.847, 95% CI = 0.706-1.270, p = 0.716). Conclusions: This meta-analysis suggests that the VDR FokI and ApaI polymorphisms are associated with susceptibility to ovarian cancer in European populations. [ABSTRACT FROM AUTHOR]