269 results found
O'Donnell CJ, Kavousi M, Smith AV, et al., 2011, Genome-Wide Association Study for Coronary Artery Calcification With Follow-Up in Myocardial Infarction, CIRCULATION, Vol: 124, Pages: 2855-U255, ISSN: 0009-7322
Herder C, Peeters W, Illig T, et al., 2011, RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies, PLOS ONE, Vol: 6, ISSN: 1932-6203
Leebeek FWG, Dehghan A, Kruip MJHA, et al., 2011, The presumed increased bleeding tendency in red-haired individuals is not associated with von Willebrand factor antigen levels in older individuals, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 2509-2511, ISSN: 1538-7933
Kiechl S, Pare G, Barbalic M, et al., 2011, Association of Variation at the ABO Locus With Circulating Levels of Soluble Intercellular Adhesion Molecule-1, Soluble P-selectin, and Soluble E-selectin A Meta-Analysis, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 4, Pages: 681-U436, ISSN: 1942-325X
Bown MJ, Jones GT, Harrison SC, et al., 2011, Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 89, Pages: 619-627, ISSN: 0002-9297
Chambers JC, Zhang W, Sehmi J, et al., 2011, Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma, NATURE GENETICS, Vol: 43, Pages: 1131-1138, ISSN: 1061-4036
Ehret GB, Munroe PB, Rice KM, et al., 2011, Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk, NATURE, Vol: 478, Pages: 103-109, ISSN: 0028-0836
Strawbridge RJ, Dupuis J, Prokopenko I, et al., 2011, Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes, Diabetes, Vol: 60, Pages: 2624-2634, ISSN: 0012-1797
OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
Bis JC, Kavousi M, Franceschini N, et al., 2011, Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque, NATURE GENETICS, Vol: 43, Pages: 940-U40, ISSN: 1061-4036
Wain LV, Verwoert GC, O'Reilly PF, et al., 2011, Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure, NATURE GENETICS, Vol: 43, Pages: 1005-U122, ISSN: 1061-4036
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans1,2,3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10−8 to P = 2.3 × 10−13) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Boeger CA, Gorski M, Li M, et al., 2011, Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD, PLOS GENETICS, Vol: 7, ISSN: 1553-7390
Butterworth AS, Braund PS, Farrall M, et al., 2011, Large-scale gene-centric analysis identifies novel variants for coronary Artery disease, PLoS Genetics, Vol: 7, ISSN: 1553-7390
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse bioc
Ricketts SL, Rensing KL, Holly JM, et al., 2011, Prospective study of insulin-like growth factor-I, insulinlike growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease, International Journal of Molecular Epidemiology and Genetics, Vol: 2, Pages: 261-285
Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% CI 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% CI 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.
Smith NL, Rice KM, Bovill EG, et al., 2011, Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis, BLOOD, Vol: 117, Pages: 6007-6011, ISSN: 0006-4971
Arking DE, Junttila MJ, Goyette P, et al., 2011, Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals, PLOS GENETICS, Vol: 7, ISSN: 1553-7390
van Hoek M, van Herpt TW, Dehghan A, et al., 2011, Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons, DIABETOLOGIA, Vol: 54, Pages: 1360-1367, ISSN: 0012-186X
Nalls MA, Couper DJ, Tanaka T, et al., 2011, Multiple Loci Are Associated with White Blood Cell Phenotypes, PLOS GENETICS, Vol: 7, ISSN: 1553-7390
Smith NL, Huffman JE, Strachan DP, et al., 2011, Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults, CIRCULATION, Vol: 123, Pages: 1864-+, ISSN: 0009-7322
Pare G, Ridker PM, Rose L, et al., 2011, Genome-Wide Association Analysis of Soluble ICAM-1 Concentration Reveals Novel Associations at the NFKBIK, PNPLA3, RELA, and SH2B3 Loci, PLOS GENETICS, Vol: 7, ISSN: 1553-7390
Schunkert H, Koenig IR, Kathiresan S, et al., 2011, Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease, NATURE GENETICS, Vol: 43, Pages: 333-U153, ISSN: 1061-4036
Speliotes EK, Yerges-Armstrong LM, Wu J, et al., 2011, Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits, PLOS Genetics, Vol: 7, ISSN: 1553-7390
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable ( approximately 26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and approximately 2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5x10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.
Dehghan A, Dupuis J, Barbalic M, et al., 2011, Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels, CIRCULATION, Vol: 123, Pages: 731-U151, ISSN: 0009-7322
Wensley F, Gao P, Burgess S, et al., 2011, Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data, British Medical Journal, Vol: 342, ISSN: 1468-5833
Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease.Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries.Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors.Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals.Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10−34) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference).Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
el Barzouhi A, Elias-Smale S, Dehghan A, et al., 2011, Renal Function Is Related to Severity of Coronary Artery Calcification in Elderly Persons: The Rotterdam Study, PLOS ONE, Vol: 6, ISSN: 1932-6203
Versmissen J, Oosterveer DM, Yazdanpanah M, et al., 2011, A frequent variant in the ABCA1 gene is associated with increased coronary heart disease risk and a better response to statin treatment in familial hypercholesterolemia patients, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 469-475, ISSN: 0195-668X
Yang Q, Koettgen A, Dehghan A, et al., 2010, Multiple Genetic Loci Influence Serum Urate Levels and Their Relationship With Gout and Cardiovascular Disease Risk Factors, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 3, Pages: 523-530, ISSN: 1942-325X
Yang Q, Köttgen A, Dehghan A, et al., 2010, Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors., Circ Cardiovasc Genet, Vol: 3, Pages: 523-530
BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
O'Seaghdha CM, Yang Q, Glazer NL, et al., 2010, Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels, HUMAN MOLECULAR GENETICS, Vol: 19, Pages: 4296-4303, ISSN: 0964-6906
Struchalin MV, Dehghan A, Witteman JCM, et al., 2010, Variance heterogeneity analysis for detection of potentially interacting genetic loci: method and its limitations, BMC GENETICS, Vol: 11, ISSN: 1471-2156
Meyer TE, Verwoert GC, Hwang S-J, et al., 2010, Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels, PLOS GENETICS, Vol: 6, ISSN: 1553-7404
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