Ealing Hospital National Health Service NHS Trust

United Kingdom

Ealing Hospital National Health Service NHS Trust

United Kingdom
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Chambers J.C.,Imperial College London | Chambers J.C.,Ealing Hospital National Health Service NHS Trust | Zhao J.,University College London | Terracciano C.M.N.,Imperial College London | And 29 more authors.
Nature Genetics | Year: 2010

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 × 10 15) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (GA) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10 5 to 10 20). SCN10A encodes Na V 1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a / mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation. © 2010 Nature America, Inc. All rights reserved.


Huang J.,Lung and Blood Institutes Framingham Heart Study | Sabater-Lleal M.,Karolinska University Hospital | Asselbergs F.W.,University Utrecht | Tregouet D.,University Pierre and Marie Curie | And 100 more authors.
Blood | Year: 2012

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery metaanalysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P < 3.4 × 10-10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P < 3.0 × 10-8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10-8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.


Peden J.F.,University of Oxford | Hopewell J.C.,University of Oxford | Saleheen D.,Center for Non Communicable Diseases Pakistan | Saleheen D.,University of Cambridge | And 109 more authors.
Nature Genetics | Year: 2011

Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD), a modest number considering the apparent heritability of CAD. All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with -4575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5- 10 8 in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility. © 2011 Nature America, Inc. All rights reserved.


Kooner J.S.,Imperial College London | Kooner J.S.,Ealing Hospital National Health Service NHS Trust | Saleheen D.,Center for Non Communicable Diseases Pakistan | Saleheen D.,University of Cambridge | And 82 more authors.
Nature Genetics | Year: 2011

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10 -4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10 -8 to P = 1.9 × 10 -11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10 -4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D. © 2011 Nature America, Inc. All rights reserved.


Nikpay M.,University of Ottawa | Goel A.,University of Oxford | Won H.-H.,The Broad Institute of MIT and Harvard | Won H.-H.,Massachusetts General Hospital | And 210 more authors.
Nature Genetics | Year: 2015

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. © 2015 Nature America, Inc.


Xi B.,Shandong University | Takeuchi F.,National Health Research Institute | Meirhaeghe A.,French Institute of Health and Medical Research | Meirhaeghe A.,Institute Pasteur Of Lille | And 20 more authors.
Clinical Endocrinology | Year: 2014

Objective Genome-wide association studies have identified many obesity/body mass index (BMI)-associated loci in Europeans and East Asians. Since then, a large number of studies have investigated the role of BMI-associated loci in the development of type 2 diabetes (T2D). However, the results have been inconsistent. The objective of this study was to investigate the associations of eleven obesity/BMI loci with T2D risk and explore how BMI influences this risk.Methods We retrieved published literature from PubMed and Embase. The pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using fixed- or random-effect models.Results In the meta-analysis of 42 studies for 11 obesity/BMI-associated loci, we observed a statistically significant association of the FTO rs9939609 polymorphism (66 425 T2D cases/239 689 normoglycaemic subjects; P = 1·00 × 10-41) and six other variants with T2D risk (17 915 T2D cases/27 531 normoglycaemic individuals: n = 40 629-130 001; all P < 0·001 for SH2B1 rs7498665, FAIM2 rs7138803, TMEM18 rs7561317, GNPDA2 rs10938397, BDNF rs925946 and NEGR1 rs2568958). After adjustment for BMI, the association remained statistically significant for four of the seven variants (all P < 0·05 for FTO rs9939609, SH2B1 rs7498665, FAIM2 rs7138803, GNPDA2 rs10938397). Subgroup analysis by ethnicity demonstrated similar results.Conclusions This meta-analysis indicates that several BMI-associated variants are significantly associated with T2D risk. Some variants increase the T2D risk independent of obesity, while others mediate this risk through obesity. © 2014 John Wiley & Sons Ltd.


PubMed | University of Turku, Kk Womens And Childrens Hospital, CNR Institute of Neuroscience, University of Houston and 76 more.
Type: Journal Article | Journal: Nature genetics | Year: 2015

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 10(-11) to 5.0 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

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