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JAMA The Journal of the American Medical Association 05/2013; 309(18):1895-6. · 30.03 Impact Factor
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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
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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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Bani Tamraz,
Hisayo Fukushima,
Alan R Wolfe,
Rüdiger Kaspera,
Rheem A Totah,
James S Floyd,
Benjamin Ma,
Catherine Chu,
Kristin D Marciante,
Susan R Heckbert, Bruce M Psaty,
Deanna L Kroetz,
Pui-Yan Kwok
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ABSTRACT: OBJECTIVE: Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. METHODS: This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. RESULTS: The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. CONCLUSION: Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.
Pharmacogenetics and Genomics 05/2013; · 3.48 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Mägi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
André Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
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ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Magi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
Andre Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
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[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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ABSTRACT: BACKGROUND
Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood.METHODS
We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant's mean systolic BP (SBP) across visits.RESULTSThe mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE).CONCLUSIONS
In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP.
American Journal of Hypertension 03/2013; · 3.18 Impact Factor
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Eleonora Porcu,
Marco Medici,
Giorgio Pistis,
Claudia B Volpato,
Scott G Wilson,
Anne R Cappola,
Steffan D Bos,
Joris Deelen,
Martin den Heijer,
Rachel M Freathy, [......],
Theo J Visser,
Bruce H R Wolffenbuttel,
Ingrid Meulenbelt,
Jerome I Rotter,
Tim D Spector,
Andrew A Hicks,
Daniela Toniolo,
Serena Sanna,
Robin P Peeters,
Silvia Naitza
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ABSTRACT: Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
PLoS Genetics 02/2013; 9(2):e1003266. · 8.69 Impact Factor
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Jason H Y Wu,
Rozenn N Lemaitre,
Ani Manichaikul,
Weihua Guan,
Toshiko Tanaka,
Millennia Foy,
Edmond K Kabagambe,
Luc Djousse,
David Siscovick,
Amanda M Fretts, [......],
Stefania Bandinelli,
David R Jacobs,
Brian L Browning,
Cathy C Laurie,
Xiangjun Gu,
Michael Y Tsai,
Lyn M Steffen,
Luigi Ferrucci,
Myriam Fornage,
Dariush Mozaffarian
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ABSTRACT: BACKGROUND: -Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease. METHODS AND RESULTS: -Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7x10(-11)) and lower 18:0(P=2.2x10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6x10(-13)) and 18:1n-9(P=2.2x10(-32)), and lower 18:0(P =1.3x10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8x10(-9)). GCKR (glucokinase regulator, P=9.8x10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1, P=5.7x10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1, P=5.7x10(-15)) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1x10(-8)). CONCLUSIONS: -Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.
Circulation Cardiovascular Genetics 01/2013; · 6.11 Impact Factor
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ABSTRACT: This study examined whether different associations between risk factors and atrial fibrillation (AF) according to race could explain the lower incidence of AF in blacks. Baseline risk factor information was obtained from interviews, clinical examinations, and echocardiography in 4,774 white and 911 black Cardiovascular Health Study participants aged 65 and older without a history of AF at baseline in 1989/90 or 1992/93. Incident AF was determined according to hospital discharge diagnosis or annual study electrocardiogram. Cox regression was used to assess associations between risk factors and race and incident AF. During a mean 11.2 years of follow-up, 1,403 whites and 182 blacks had incident AF. Associations between all examined risk factors were similar in both races, except left ventricular posterior wall thickness, which was more strongly associated with AF in blacks (per 0.2 cm, blacks: hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.44-2.06; whites: HR = 1.30, 95% CI = 1.18-1.43). Overall, the relative risk of AF was 25% lower in blacks than whites after adjustment for age and sex (HR = 0.75, 95% CI = 0.64-0.87) and 45% lower after adjustment for all considered risk factors (HR = 0.55, 95% CI = 0.35-0.88). Different associations of the considered risk factors and incident AF by race do not explain the lower incidence of AF in blacks.
Journal of the American Geriatrics Society 01/2013; · 3.74 Impact Factor
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David R Crosslin,
Andrew McDavid,
Noah Weston,
Xiuwen Zheng,
Eugene Hart,
Mariza de Andrade,
Iftikhar J Kullo,
Catherine A McCarty,
Kimberly F Doheny,
Elizabeth Pugh, [......],
Dan L Longo,
Jacqueline C M Witteman, Bruce M Psaty,
Luigi Ferrucci,
Tamara B Harris,
Christopher J O'Donnell,
Santhi K Ganesh,
Eric B Larson,
Chris S Carlson,
Gail P Jarvik
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ABSTRACT: With white blood cell count (WBC) emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases, such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11,014 subjects in the electronic Medical Records and Genomics (eMERGE) Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (p-value=2.78e-16, β=-0.22). Other monocyte associations include novel missense variants in the chemokine binding protein 2 (CCBP2) gene (p-value=1.88e-7, β=0.30) and a region of replication found in ribophorin I (RPN1) (p-value=2.63e-16, β=-0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA2 gene, which has been previously shown to be associated with coronary heart disease. On chromosome 9 we found a novel association in the prostaglandin reductase 1 (PTGR1) gene (p-value=2.29e-7, β=0.16), which is downstream from lysophosphatidic acid receptor 1 (LPAR1). This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (p-value=5.68e-17, β=-0.23) at the ITGA4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
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Andrew D Johnson,
Shih-Jen Hwang,
Arend Voorman,
Alanna Morrison,
Gina M Peloso,
Yi-Hsiang Hu,
George Thanassoulis,
Christopher Newton-Cheh,
Ian S Rogers,
Udo Hoffman,
Jane E Freedman,
Caroline S Fox, Bruce M Psaty,
Eric Boerwinkle,
L Adrienne Cupples,
Christopher J O'Donnell
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ABSTRACT: BACKGROUND: 9p21.3 is among the most strongly replicated regions for cardiovascular disease (CVD). There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical CVD and its risk factors, and with copy number variation and gene expression, in the Framingham Heart Study (FHS). METHODS AND RESULTS: We sequenced 281 individuals (n=94 with myocardial infarction, n=94 with high coronary artery calcium levels, and n=93 controls free of elevated coronary artery calcium or myocardial infarction) followed by genotyping and association in >7,000 additional FHS individuals. We assessed genetic associations with clinical and subclinical CVD, risk factor phenotypes, and gene expression levels of protein-coding genes CDKN2A and CDKN2B as well as the non-coding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters, and no evidence for association with traditional CVD risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or CNV events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B. CONCLUSIONS: Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations, and provide further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.
Circulation 01/2013; · 14.74 Impact Factor
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John R B Perry,
Tanguy Corre,
Tõnu Esko,
Daniel I Chasman,
Krista Fischer,
Nora Franceschini,
Chunyan He,
Zoltan Kutalik,
Massimo Mangino,
Lynda M Rose, [......],
Tim D Spector,
Kari Stefansson,
Anthony J Swerdlow,
Unnur Thorsteinsdottir,
Rob M Van Dam,
André G Uitterlinden,
Jenny A Visser,
Peter Vollenweider,
Daniela Toniolo,
Anna Murray
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ABSTRACT: Early menopause affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of early menopause is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies in 3493 early menopause cases and 13598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait were also associated with early menopause and POI (Primary Ovarian Insufficiency). Thus early menopause has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the SNP arrays was estimated to account for approximately 30% of the variance in EM. The association between the combined 17 variants and the risk of early menopause was greater than the best validated non-genetic risk factor, smoking.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
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Elizabeth G Holliday,
Albert V Smith,
Belinda K Cornes,
Gabriëlle H S Buitendijk,
Richard A Jensen,
Xueling Sim,
Thor Aspelund,
Tin Aung,
Paul N Baird,
Eric Boerwinkle, [......],
Sophia Xie,
Johannes R Vingerling,
Caroline C W Klaver,
E Shyong Tai,
David Siscovick,
Ronald Klein,
Mary Frances Cotch,
Tien Y Wong,
John Attia,
Jie Jin Wang
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ABSTRACT: Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
PLoS ONE 01/2013; 8(1):e53830. · 4.09 Impact Factor
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Richard A Jensen,
Xueling Sim,
Xiaohui Li,
Mary Frances Cotch,
M Kamran Ikram,
Elizabeth G Holliday,
Gudny Eiriksdottir,
Tamara B Harris,
Fridbert Jonasson,
Barbara E K Klein, [......],
Kerri L Wiggins,
Jane Z Kuo,
Cornelia M van Duijn,
Vilmundur Gudnason,
Ronald Klein,
David S Siscovick,
Jerome I Rotter,
E Shong Tai,
Johannes Vingerling,
Tien Y Wong
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ABSTRACT: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
PLoS ONE 01/2013; 8(2):e54232. · 4.09 Impact Factor
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Sidharth A Shah,
David M Herrington,
Timothy D Howard,
Jasmin Divers,
Donna K Arnett,
Greg L Burke,
Weng Hong Kao,
Xiuqing Guo,
David S Siscovick,
Aravinda Chakravarti,
Joao A Lima, Bruce M Psaty,
Gordon F Tomaselli,
Stephen S Rich,
Donald W Bowden,
Wendy Post
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ABSTRACT: QT is a risk factor for sudden cardiac death (SCD). A genome-wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used the Multi-Ethnic Study of Atherosclerosis to examine association of QT with NOS1AP variants in an ethnically diverse cohort.
Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African Americans (AFA), Hispanics (HIS), and Chinese (CHN)), age 45-84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates.
More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9 msec, P = 7.20 × 10-7). Significant associations in CAU and HIS were located at the 5' end, while associations in CHN were located at the 3' end.
NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3' end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. In addition, investigations are needed across ethnically diverse population cohorts.
Annals of Noninvasive Electrocardiology 01/2013; 18(1):29-40. · 1.10 Impact Factor
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Amanda M Fretts,
Dariush Mozaffarian,
David S Siscovick,
Susan R Heckbert,
Barbara McKnight,
Irena B King,
Eric B Rimm, Bruce M Psaty,
Frank M Sacks,
Xiaoling Song,
Donna Spiegelman,
Rozenn N Lemaitre
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ABSTRACT: Few studies have examined the relationship of α-linolenic acid (ALA 18:3n-3), an intermediate-chain essential n-3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).
The study population included participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95% CI, 0.90 to 1.37), 1.09 (95% CI, 0.88 to 1.35), and 0.92 (95% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.
Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.
Journal of the American Heart Association. 01/2013; 2(1):e003814.
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Anna Köttgen,
Eva Albrecht,
Alexander Teumer,
Veronique Vitart,
Jan Krumsiek,
Claudia Hundertmark,
Giorgio Pistis,
Daniela Ruggiero,
Conall M O'Seaghdha,
Toomas Haller, [......],
Nicole Soranzo,
Daniela Toniolo,
Daniel I Chasman,
Olli Raitakari,
W H Linda Kao,
Marina Ciullo,
Caroline S Fox,
Mark Caulfield,
Murielle Bochud,
Christian Gieger
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ABSTRACT: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Nature genetics. 01/2013; 45(2):145-54.
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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
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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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Anna Köttgen,
Eva Albrecht,
Alexander Teumer,
Veronique Vitart,
Jan Krumsiek,
Claudia Hundertmark,
Giorgio Pistis,
Daniela Ruggiero,
Conall M O'Seaghdha,
Toomas Haller, [......],
Nicole Soranzo,
Daniela Toniolo,
Daniel I Chasman,
Olli Raitakari,
W H Linda Kao,
Marina Ciullo,
Caroline S Fox,
Mark Caulfield,
Murielle Bochud,
Christian Gieger
[show abstract]
[hide abstract]
ABSTRACT: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Nature Genetics 12/2012; · 35.53 Impact Factor
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Bing Yu,
Maja Barbalic,
Ariel Brautbar,
Vijay Nambi,
Ron C Hoogeveen,
Weihong Tang,
Thomas H Mosley,
Jerome I Rotter,
Christopher R Defilippi,
Christopher J O'Donnell,
Sekar Kathiresan,
Ken Rice,
Susan R Heckbert,
Christie M Ballantyne, Bruce M Psaty,
Eric Boerwinkle
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ABSTRACT: BACKGROUND: -High levels of cardiac troponin T measured by a highly sensitive assay (hs-cTnT) are strongly associated with incident coronary heart disease (CHD) and heart failure (HF). No large-scale genome-wide association study (GWAS) of hs-cTnT has been reported to date. We sought to identify novel genetic variants that are associated with hs-cTnT levels. METHODS AND RESULTS: -We performed a GWAS in 9,491 European-Americans and 2,053 African-Americans free of CHD and HF from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). GWASs were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum, and then across race strata to produce overall estimates and p-values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374, p = 9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Over-expression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99(th) percentile cut-point detected a significant association at 1q32 (rs12564445, p = 4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated SNPs were not associated with CHD in a large case-control study, but rs12564445 was significantly associated with incident HF in ARIC European-Americans (HR = 1.16, p-value = 0.004). CONCLUSIONS: -We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.
Circulation Cardiovascular Genetics 12/2012; · 6.11 Impact Factor
