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Weihong Tang,
Martina Teichert,
Daniel I Chasman,
John A Heit,
Pierre-Emmanuel Morange,
Guo Li,
Nathan Pankratz,
Frank W Leebeek,
Guillaume Paré,
Mariza de Andrade, [......],
Xiaoxiao Kong,
Russell P Tracy,
Eric Boerwinkle,
Jerome I Rotter,
David-Alexandre Trégouët,
Daan W Loth,
Bruno H Ch Stricker,
Paul M Ridker,
Aaron R Folsom, Nicholas L Smith
[show abstract]
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ABSTRACT: Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
Genetic Epidemiology 05/2013; · 3.44 Impact Factor
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Ervin R Fox,
Solomon K Musani,
Maja Barbalic,
Honghuang Lin,
Bing Yu,
Kofo O Ogunyankin, Nicholas L Smith,
Abdullah Kutlar,
Nicole L Glazer,
Wendy S Post, [......],
Alanna C Morrison,
Gerardo Heiss,
J Jeffrey Carr,
Russell P Tracy,
Thomas H Mosley,
Herman A Taylor,
Bruce M Psaty,
Susan R Heckbert,
Thomas P Cappola,
Ramachandran S Vasan
[show abstract]
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ABSTRACT: BACKGROUND: -Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study. METHODS AND RESULTS: -Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 x10(-07)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43x10(-07)) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 x10(-07)) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 x10(-08)) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 x10(-07)) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN. CONCLUSIONS: -In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
Circulation Cardiovascular Genetics 12/2012; · 6.11 Impact Factor
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Jie Huang,
Maria Sabater-Lleal,
Folkert W Asselbergs,
David Tregouet,
So-Youn Shin,
Jingzhong Ding,
Jens Baumert,
Tiphaine Oudot-Mellakh,
Lasse Folkersen,
Andrew D Johnson, [......],
Per Eriksson,
Francois Cambien,
Cardiogenics Consortium,
Pierre-Emmanuel Morange,
Wolfgang Koenig,
Nicole Soranzo,
Pim van der Harst,
Yongmei Liu,
Christopher J O'Donnell,
Anders Hamsten
[show abstract]
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ABSTRACT: 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 meta-analysis was performed in 19,599 subjects, followed by replication analysis of genome-wide significant (P<5x10(-8)) single nucleotide polymorphisms (SNPs) in 10,796 independent samples. We further examined associations with type 2 diabetes (T2D) and coronary artery disease (CAD), 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=3.4x10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P=3.0x10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P=2.9x10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with T2D and CAD at ARNTL (P<0.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL, and a SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
Blood 09/2012; · 9.90 Impact Factor
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[show abstract]
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ABSTRACT: BACKGROUND: After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions. OBJECTIVE: To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated. DESIGN: Population-based inception cohort study. PARTICIPANTS: Enrollees in Group Health, an integrated health care system, aged 30-84 with newly diagnosed AF in 2001-2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385). MAIN MEASURES: Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6-36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). KEY RESULTS: Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5-24.9 kg/m(2)), BMI levels of 25.0-29.9 (overweight), 30.0-34.9 (obese 1), 35.0-39.9 (obese 2), and ≥ 40.0 kg/m(2) (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF. CONCLUSIONS: For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.
Journal of General Internal Medicine 09/2012; · 2.83 Impact Factor
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ABSTRACT: Transforming growth factor-beta1 (TGF-B1) is a highly pleiotropic cytokine whose functions include a central role in the induction of fibrosis.
To investigate the hypothesis that elevated plasma levels of TGF-B1 are positively associated with incident heart failure (HF).
The hypotheses were tested using a two-phase case-control study design, ancillary to the Cardiovascular Health Study - a longitudinal, population-based cohort study. Cases were defined as having an incident HF event after their 1992-1993 exam and controls were free of HF at follow-up. TGF-B1 was measured using plasma collected in 1992-1993 and data from 89 cases and 128 controls were used for analysis. The association between TGF-B1 and risk of HF was evaluated using the weighted likelihood method, and odds ratios (OR) for risk of HF were calculated for TGF-B1 as a continuous linear variable and across quartiles of TGF-B1.
The OR for HF was 1.88 (95% confidence intervals [CI] 1.26-2.81) for each nanogram increase in TGF-B1, and the OR for the highest quartile (compared to the lowest) of TGF-B1 was 5.79 (95% CI 1.65-20.34), after adjustment for age, sex, C-reactive protein, platelet count and digoxin use. Further adjustment with other covariates did not change the results.
Higher levels of plasma TGF-B1 were associated with an increased risk of incident heart failure among older adults. However, further study is needed in larger samples to confirm these findings.
Cytokine 08/2012; 60(2):341-5. · 3.02 Impact Factor
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Alisa K Manning,
Marie-France Hivert,
Robert A Scott,
Jonna L Grimsby,
Nabila Bouatia-Naji,
Han Chen,
Denis Rybin,
Ching-Ti Liu,
Lawrence F Bielak,
Inga Prokopenko, [......],
Tatijana Zemunik,
Lina Zgaga,
Nicholas J Wareham,
Mark I McCarthy,
Ines Barroso,
Richard M Watanabe,
Jose C Florez,
Josée Dupuis,
James B Meigs,
Claudia Langenberg
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ABSTRACT: Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Nature Genetics 05/2012; 44(6):659-69. · 35.53 Impact Factor
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Patrick T Ellinor,
Kathryn L Lunetta,
Christine M Albert,
Nicole L Glazer,
Marylyn D Ritchie,
Albert V Smith,
Dan E Arking,
Martina Müller-Nurasyid,
Bouwe P Krijthe,
Steven A Lubitz, [......],
Bruno H Ch Stricker,
Stephan B Felix,
Alvaro Alonso,
Dawood Darbar,
John Barnard,
Daniel I Chasman,
Susan R Heckbert,
Emelia J Benjamin,
Vilmundur Gudnason,
Stefan Kääb
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ABSTRACT: Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
Nature Genetics 04/2012; 44(6):670-5. · 35.53 Impact Factor
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Zari Dastani,
Marie-France Hivert,
Nicholas Timpson,
John R B Perry,
Xin Yuan,
Robert A Scott,
Peter Henneman,
Iris M Heid,
Jorge R Kizer,
Leo-Pekka Lyytikäinen, [......],
Eric E Schadt,
David P Strachan,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Sekar Kathiresan
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ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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Nicholette D Palmer,
Caitrin W McDonough,
Pamela J Hicks,
Bong H Roh,
Maria R Wing,
S Sandy An,
Jessica M Hester,
Jessica N Cooke,
Meredith A Bostrom,
Megan E Rudock, [......],
Angelo Scuteri,
David Schlessinger,
Manuela Uda,
Aimo Ruokonen,
Marjo-Riitta Jarvelin,
Dawn M Waterworth,
Peter Vollenweider,
Leena Peltonen,
Vincent Mooser,
Robert Sladek
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ABSTRACT: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
PLoS ONE 01/2012; 7(1):e29202. · 4.09 Impact Factor
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Harald Grallert,
Josée Dupuis,
Joshua C Bis,
Abbas Dehghan,
Maja Barbalic,
Jens Baumert,
Chen Lu, Nicholas L Smith,
André G Uitterlinden,
Robert Roberts, [......],
Jennifer F Yamamoto,
Jerome I Rotter,
Martin G Larson,
Alexandre F R Stewart,
Eric Boerwinkle,
Jacqueline C M Witteman,
Russell P Tracy,
Wolfgang Koenig,
Emelia J Benjamin,
Christie M Ballantyne
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ABSTRACT: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.
Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
European Heart Journal 01/2012; 33(2):238-51. · 10.48 Impact Factor
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Evan L Thacker,
Bruce M Psaty,
Barbara McKnight,
Susan R Heckbert,
W T Longstreth,
Kenneth J Mukamal,
James B Meigs,
Ian H de Boer,
Edward J Boyko,
Mercedes R Carnethon,
Jorge R Kizer,
Russell P Tracy, Nicholas L Smith,
David S Siscovick
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ABSTRACT: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults.
Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance.
Analyses included 3442 participants (42% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95% CI, 0.84-1.46).
In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.
Stroke 12/2011; 42(12):3347-51. · 5.73 Impact Factor
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Gary F Mitchell,
Germaine C Verwoert,
Kirill V Tarasov,
Aaron Isaacs,
Albert V Smith,
Yasmin,
Ernst R Rietzschel,
Toshiko Tanaka,
Yongmei Liu,
Afshin Parsa, [......],
John R Cockcroft,
Vilmundur Gudnason,
Guy G De Backer,
Luigi Ferrucci,
Tamara B Harris,
Alan R Shuldiner,
Cornelia M van Duijn,
Daniel Levy,
Edward G Lakatta,
Jacqueline C M Witteman
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ABSTRACT: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004).
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
Circulation Cardiovascular Genetics 11/2011; 5(1):81-90. · 6.11 Impact Factor
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Louise V Wain,
Germaine C Verwoert,
Paul F O'Reilly,
Gang Shi,
Toby Johnson,
Andrew D Johnson,
Murielle Bochud,
Kenneth M Rice,
Peter Henneman,
Albert V Smith, [......],
Vilmundur Gudnason,
Christopher Newton-Cheh,
Daniel Levy,
Patricia B Munroe,
Bruce M Psaty,
Mark J Caulfield,
Dabeeru C Rao,
Martin D Tobin,
Paul Elliott,
Cornelia M van Duijn
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ABSTRACT: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. 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.
Nature Genetics 09/2011; 43(10):1005-11. · 35.53 Impact Factor
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Georg B Ehret,
Patricia B Munroe,
Kenneth M Rice,
Murielle Bochud,
Andrew D Johnson,
Daniel I Chasman,
Albert V Smith,
Martin D Tobin,
Germaine C Verwoert,
Shih-Jen Hwang, [......],
Marjo-Riitta Järvelin,
Bruce M Psaty,
Gonçalo R Abecasis,
Aravinda Chakravarti,
Paul Elliott,
Cornelia M van Duijn,
Christopher Newton-Cheh,
Daniel Levy,
Mark J Caulfield,
Toby Johnson
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[hide abstract]
ABSTRACT: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Nature 09/2011; 478(7367):103-9. · 36.28 Impact Factor
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Kira C Taylor,
Leslie A Lange,
Delilah Zabaneh,
Ethan Lange,
Brendan J Keating,
Weihong Tang, Nicholas L Smith,
Joseph A Delaney,
Meena Kumari,
Aroon Hingorani,
Kari E North,
Mika Kivimaki,
Russell P Tracy,
Christopher J O'Donnell,
Aaron R Folsom,
David Green,
Steve E Humphries,
Alexander P Reiner
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ABSTRACT: Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
Human Molecular Genetics 06/2011; 20(17):3525-34. · 7.64 Impact Factor
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Myriam Fornage,
Stephanie Debette,
Joshua C Bis,
Helena Schmidt,
M Arfan Ikram,
Carole Dufouil,
Sigurdur Sigurdsson,
Thomas Lumley,
Anita L DeStefano,
Franz Fazekas, [......],
Eric Boerwinkle,
Bruce M Psaty,
Sudha Seshadri,
Christophe Tzourio,
Monique M B Breteler,
Thomas H Mosley,
Reinhold Schmidt,
W T Longstreth,
Charles DeCarli,
Lenore J Launer
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ABSTRACT: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
Annals of Neurology 06/2011; 69(6):928-39. · 11.09 Impact Factor
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Nicholas L Smith,
Jennifer E Huffman,
David P Strachan,
Jie Huang,
Abbas Dehghan,
Stella Trompet,
Lorna M Lopez,
So-Youn Shin,
Jens Baumert,
Veronique Vitart, [......],
Bruce M Psaty,
James F Wilson,
Gordon D O Lowe,
Christopher J O'Donnell,
Jacqueline C M Witteman,
J Wouter Jukema,
Ian J Deary,
Nicole Soranzo,
Wolfgang Koenig,
Caroline Hayward
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ABSTRACT: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.
Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
Circulation 05/2011; 123(17):1864-72. · 14.74 Impact Factor
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ABSTRACT: Automated pharmacy databases are increasingly available for assessing medication use, but research on the validity of these data is incomplete. This study aimed to measure agreement on warfarin and aspirin use between medical records and automated pharmacy data among patients with newly detected atrial fibrillation (AF).
Patients with newly detected AF (n = 1953) were previously identified in a cohort study at Group Health (GH) in Washington State. Medical records were reviewed for information on risk factors and medication use, as well as clinical care during the 6 months after AF onset. Medication data were also obtained from the GH pharmacy database. We determined the sensitivity, specificity, and positive predictive value (PPV) as measures of the validity of the GH pharmacy database as compared with medical records for warfarin and aspirin use during the first 6 and 3 months after AF onset. We also calculated the κ statistic.
For warfarin use, in comparison with the medical record review, the sensitivity, specificity, and PPV for the GH pharmacy database were excellent, and agreement was almost perfect in the 3- and 6-month periods after AF onset (κ = 0.92 and 0.93, respectively). For aspirin use, the GH pharmacy database had low sensitivity but high specificity, and agreement was only fair for these two periods (κ = 0.28 and 0.31, respectively).
The GH pharmacy database is a valuable source of data for pharmacoepidemiologic research on warfarin use among patients with AF. However, the database cannot be recommended for assessment of aspirin use. Copyright © 2010 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety 03/2011; 20(3):313-6. · 2.53 Impact Factor
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Abbas Dehghan,
Josée Dupuis,
Maja Barbalic,
Joshua C Bis,
Gudny Eiriksdottir,
Chen Lu,
Niina Pellikka,
Henri Wallaschofski,
Johannes Kettunen,
Peter Henneman, [......],
Bruce M Psaty,
Vilmundur Gudnason,
Paul M Ridker,
Georg Homuth,
Wolfgang Koenig,
Christie M Ballantyne,
Jacqueline C M Witteman,
Emelia J Benjamin,
Markus Perola,
Daniel I Chasman
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ABSTRACT: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.
We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.
We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
Circulation 02/2011; 123(7):731-8. · 14.74 Impact Factor
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Christian Gieger,
Aparna Radhakrishnan,
Ana Cvejic,
Weihong Tang,
Eleonora Porcu,
Giorgio Pistis,
Jovana Serbanovic-Canic,
Ulrich Elling,
Alison H Goodall,
Yann Labrune, [......],
Inga Prokopenko,
Derek Stemple,
Daniela Toniolo,
Lorenz Wernisch,
Serena Sanna,
Andrew A Hicks,
Augusto Rendon,
Manuel A Ferreira,
Willem H Ouwehand,
Nicole Soranzo
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ABSTRACT: Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
Nature 01/2011; 480(7376):201-8. · 36.28 Impact Factor
