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Jane F Ferguson,
Gregory J Matthews,
Raymond R Townsend,
Dominic S Raj,
Peter A Kanetsky,
Matthew Budoff,
Michael J Fischer,
Sylvia E Rosas,
Radhika Kanthety,
Mahboob Rahman, [......],
Akinlolu O Ojo,
John Flack,
Alan S Go,
Crystal A Gadegbeku,
Jackson T Wright,
Danish Saleheen,
Harold I Feldman,
Daniel J Rader,
Andrea S Foulkes,
Muredach P Reilly
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ABSTRACT: OBJECTIVES: To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (∼2,100 genes; ∼50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885). RESULTS: Of 268 SNPs reaching P <5x10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
Journal of the American College of Cardiology 05/2013; · 14.16 Impact Factor
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Santhi K Ganesh,
Vinicius Tragante,
Wei Guo,
Yiran Guo,
Matthew B Lanktree,
Erin N Smith,
Toby Johnson,
Berta Almoguera Castillo,
John Barnard,
Jens Baumert, [......],
Pim van der Harst,
Yvonne T van der Schouw,
Nilesh J Samani,
Andrew D Johnson,
Patricia B Munroe,
Paul I W de Bakker,
Xiaofeng Zhu,
Daniel Levy,
Brendan J Keating,
Folkert W Asselbergs
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ABSTRACT: Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 single nucleotide polymorphisms (SNPs) that capture variation in ∼2,100 candidate genes for cardiovascular phenotypes in 61,619 individuals of European ancestry from cohort studies in the US and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed ten previously known loci associated with SBP, DBP, MAP, or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P value<2.4 x 10(-6)). We then replicated these associations in an independent set of 65,886 individuals of European ancestry. Findings from eQTL analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease, left ventricular hypertrophy, or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
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Folkert W Asselbergs,
Yiran Guo,
Erik P A van Iperen,
Suthesh Sivapalaratnam,
Vinicius Tragante,
Matthew B Lanktree,
Leslie A Lange,
Berta Almoguera,
Yolande E Appelman,
John Barnard, [......],
Nilesh J Samani,
Alex P Reiner,
Robert A Hegele,
John J P Kastelein,
Aroon D Hingorani,
Philippa J Talmud,
Hakon Hakonarson,
Clara C Elbers,
Brendan J Keating,
Fotios Drenos
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ABSTRACT: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
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Richa Saxena,
Clara C Elbers,
Yiran Guo,
Inga Peter,
Tom R Gaunt,
Jessica L Mega,
Matthew B Lanktree,
Archana Tare,
Berta Almoguera Castillo,
Yun R Li, [......],
Paul I W de Bakker,
Jeanne McCaffery,
Cisca Wijmenga,
Marc S Sabatine,
James G Wilson,
Alex Reiner,
Donald W Bowden,
Hakon Hakonarson,
David S Siscovick,
Brendan J Keating
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ABSTRACT: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
The American Journal of Human Genetics 02/2012; 90(3):410-25. · 10.60 Impact Factor
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Christopher J O'Donnell,
Maryam Kavousi,
Albert V Smith,
Sharon L R Kardia,
Mary F Feitosa,
Shih-Jen Hwang,
Yan V Sun,
Michael A Province,
Thor Aspelund,
Abbas Dehghan, [......],
Andre G Uitterlinden,
Joseph M Massaro,
Julie Cunningham,
Tamara B Harris,
Albert Hofman,
Patricia A Peyser,
Ingrid B Borecki,
L Adrienne Cupples,
Vilmundur Gudnason,
Jacqueline C M Witteman
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ABSTRACT: Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI.
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
Circulation 12/2011; 124(25):2855-64. · 14.74 Impact Factor
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ABSTRACT: We carried out a genome-wide association study of serum aspartate aminotransferase (AST) activity in 866 Amish participants of the Heredity and Phenotype Intervention Heart Study and identified significant association of AST activity with a cluster of single nucleotide polymorphisms located on chromosome 10q24.1 (peak association was rs17109512; P=2.80E-14), in the vicinity of GOT1, the gene encoding cytosolic AST (cAST). Sequencing of GOT1 revealed an in-frame deletion of three nucleic acids encoding asparagine at position 389 c.1165_1167delAAC (p.Asn389del) in the gene. Deletion carriers had significantly lower AST activity levels compared with homozygotes for the common allele (mean±s.d.: 10.0±2.8 versus 18.8±5.2 U l(-1); P=2.80E-14). Further genotyping of the deletion in other Amish samples (n=1932) identified an additional 20 carriers (minor allele frequency (MAF)=0.0052). The deletion was not detected in 647 outbred Caucasians. Asn at codon 389 is conserved among known mammalian cASTs. In vitro transient transfection of wild-type and mutant cAST indicated that mutant cAST protein was barely detectable in the cells. Furthermore, even after correction for cAST expression, mutant cAST had markedly diminished enzymatic activity. Remarkably, we did not find any association between the deletion and metabolic traits including serum fasting glucose or insulin, fasting and post-meal lipids, inflammatory markers, or sub-clinical markers of cardiovascular disease. In conclusion, we discovered a rare in-frame deletion in GOT1 gene, which inactivates cAST enzyme in the Old Order Amish. This finding will help us to understand structure and function of the enzyme and would be useful for predicting serum AST levels.
Journal of Human Genetics 09/2011; 56(11):801-5. · 2.57 Impact Factor
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Matthew B Lanktree,
Yiran Guo,
Muhammed Murtaza,
Joseph T Glessner,
Swneke D Bailey,
N Charlotte Onland-Moret,
Guillaume Lettre,
Halit Ongen,
Ramakrishnan Rajagopalan,
Toby Johnson, [......],
Wolfgang Koenig,
Tom R Gaunt,
Sonia S Anand,
Yvonne T van der Schouw,
Nicole Soranzo,
Garret A Fitzgerald,
Alex Reiner,
Robert A Hegele,
Hakon Hakonarson,
Brendan J Keating
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ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
The American Journal of Human Genetics 01/2011; 88(1):6-18. · 10.60 Impact Factor
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Haiqing Shen,
Lawrence F Bielak,
Jane F Ferguson,
Elizabeth A Streeten,
Laura M Yerges-Armstrong,
Jie Liu,
Wendy Post,
Jeffery R O'Connell,
James E Hixson,
Sharon L R Kardia, [......],
Nehal N Mehta,
Mingyao Li,
Daniel L Koller,
Hakan Hakonarson,
Brendan J Keating,
Daniel J Rader,
Alan R Shuldiner,
Patricia A Peyser,
Muredach P Reilly,
Braxton D Mitchell
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ABSTRACT: The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).
We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1, P=0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P=0.007) and Penn Coronary Artery Calcification (P=0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10(-6).
A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.
Arteriosclerosis Thrombosis and Vascular Biology 12/2010; 30(12):2648-54. · 6.37 Impact Factor
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Haiqing Shen,
Coleen M Damcott,
Evadnie Rampersaud,
Toni I Pollin,
Richard B Horenstein,
Patrick F McArdle,
Patricia A Peyser,
Lawrence F Bielak,
Wendy S Post,
Yen-Pei C Chang,
Kathleen A Ryan,
Michael Miller,
John A Rumberger,
Patrick F Sheedy,
John Shelton,
Jeffrey R O'Connell,
Alan R Shuldiner,
Braxton D Mitchell
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ABSTRACT: Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels.
To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals.
From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10(-68)). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10(-36)). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10(-6) in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400).
The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.
Archives of internal medicine 11/2010; 170(20):1850-5. · 11.46 Impact Factor
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Kiran Musunuru,
Wendy S Post,
William Herzog, Haiqing Shen,
Jeffrey R O'Connell,
Patrick F McArdle,
Kathleen A Ryan,
Quince Gibson,
Yu-Ching Cheng,
Elizabeth Clearfield, [......],
Qiong Yang,
Christopher J O'Donnell,
Diane M Becker,
Lisa R Yanek,
Lewis C Becker,
Nauder Faraday,
Lawrence F Bielak,
Patricia A Peyser,
Alan R Shuldiner,
Braxton D Mitchell
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ABSTRACT: Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations.
Subjects in the initial population included 1402 asymptomatic Amish adults in whom we measured platelet reactivity (n=788) and coronary artery calcification (CAC) (n=939). Platelet reactivity on agonist stimulation was measured by impedance aggregometry, and CAC was measured by electron beam CT. Twenty-nine SNPs at the 9p21.3 locus were genotyped using the Affymetrix 500K array. Twelve correlated SNPs in the locus were significantly associated with platelet reactivity (all P≤0.001). The SNP most strongly associated with platelet reactivity, rs10965219 (P=0.0002), also was associated with CAC (P=0.002) along with 9 other SNPs (all P<0.004). Association of rs10965219 with platelet reactivity persisted after adjustment for CAC, a measure of underlying atherosclerotic burden known to affect platelet reactivity. We then tested rs10965219 for association with platelet function in 2364 subjects from the Framingham Heart Study and 1169 subjects from the Genetic Study of Aspirin Responsiveness. The rs10965219 G allele (frequency ≈51% across all 3 populations) was significantly associated with higher platelet reactivity in the Framingham Heart Study (P=0.001) and trended toward higher reactivity in the Genetic Study of Aspirin Responsiveness (P=0.087); the combined P value for metaanalysis was 0.0002.
These results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity.
Circulation Cardiovascular Genetics 10/2010; 3(5):445-53. · 6.11 Impact Factor
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Nicole Hoppman,
John C McLenithan,
Daniel J McBride, Haiqing Shen,
Jan Bruder,
Richard L Bauer,
John R Shaffer,
Jie Liu,
Elizabeth A Streeten,
Alan R Shuldiner,
Candace M Kammerer,
Braxton D Mitchell
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ABSTRACT: We previously detected strong evidence for linkage of forearm bone mineral density (BMD) to chromosome 4p (lod=4.3) in a set of 29 large Mexican American families. Fibroblast growth factor binding protein 1 (FGFBP1) is a strong candidate gene for bone homeostasis in this region. We sequenced the coding region of FGFBP1 in a subset of our Mexican American study population and performed association studies with BMD on SNPs genotyped in the entire cohort. We then attempted to replicate these findings in an independent study cohort and performed in vitro functional studies on replicated, potentially functional polymorphisms using a luciferase reporter construct to evaluate influence on gene expression. Several SNPs spanning the gene, all in one large block of linkage disequilibrium, were significantly associated with BMD at various skeletal sites (n=872, p=0.001-0.04). The associations were then replicated in an independent population of European ancestry (n=972; p=0.02-0.04). Sex-stratified association analyses in both study populations suggest this association is much stronger in men. Subsequent luciferase reporter gene assays revealed marked differences in FGFBP1 expression among the three common haplotypes. Further experiments revealed that a promoter polymorphism, rs12503796, results in decreased expression of FGFBP1 and inhibits upregulation of the gene by testosterone in vitro. Collectively, these findings suggest that sequence variation in FGFBP1 may contribute to variation in BMD, possibly influencing osteoporosis risk.
Bone 05/2010; 47(2):272-80. · 4.02 Impact Factor
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ABSTRACT: Matrix metalloproteinase (MMP)-1 may play a role in cardiovascular disease susceptibility by influencing plaque rupture via its ability to degrade extracellular collagens.
We performed a genome-wide association analysis of circulating MMP-1 levels using 500 K single-nucleotide polymorphisms (SNPs) to identify genes influencing variation in serum MMP-1 levels in 778 healthy Amish adults. Serum MMP-1 levels, logarithm transformed, and adjusted for age and sex, were screened for association with SNPs using mixed-model variance components to account for familial relatedness. Median MMP-1 level was 3.05 ng/mL (interquartile range: 1.82 to 5.04 ng/mL) with an estimated heritability of 81% (P<0.0001). Serum MMP-1 levels were strongly associated with a cluster of 179 SNPs extending over an 11.5-megabase region on chromosome 11q. The peak association was with rs495366 (P = 5.73 x 10(-34)), located within the region between MMP-1 and MMP-3 and having a minor allele frequency of 0.36. Two other SNPs within the 11q region, rs12289128 and rs11226373, were strongly associated with MMP-1 levels after accounting for rs495366 (P < or = 10(-7)). These 3 SNPs explained 31% of the variance in MMP-1 levels after adjusting for age and sex.
This study provides strong evidence that the serum MMP-1 level is highly heritable and that SNPs near MMPs on chromosome 11q explain a significant portion of the variation in MMP-1 levels. Identification of the genetic variants that influence MMP-1 levels may provide insights into genetic mechanisms of cardiovascular disease.
Circulation Cardiovascular Genetics 08/2009; 2(4):329-37. · 6.11 Impact Factor
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ABSTRACT: Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and US Utah participants in the International HapMap project (abbreviated CEU) using a high-density single nucleotide polymorphism (SNP) map. Overall, the allele (and haplotype) frequency distributions and LD profiles were remarkably similar between these two populations. For example, the median absolute allele frequency difference for autosomal SNPs was 0.05, with an inter-quartile range of 0.02-0.09, and for autosomal SNPs 10-20 kb apart with common alleles (minor allele frequency > or =0.05), the LD measure r(2) was at least 0.8 for 15 and 14% of SNP pairs in the OOA and CEU, respectively. Moreover, tag SNPs selected from the HapMap CEU sample captured a substantial portion of the common variation in the OOA ( approximately 88%) at r(2) > or =0.8. These results suggest that the OOA and CEU may share similar LD profiles for other common but untyped SNPs. Thus, in the context of the common variant-common disease hypothesis, genetic variants discovered in gene mapping studies in the OOA may generalize to other populations.
Genetic Epidemiology 08/2009; 34(2):146-50. · 3.44 Impact Factor
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Haiqing Shen,
William Herzog,
MaryAnn Drolet,
Ruth Pakyz,
Sylvia Newcomer,
Paul Sack,
Heidi Karon,
Kathleen A Ryan,
Yiju Zhao,
Xiaolian Shi,
Braxton D Mitchell,
Alan R Shuldiner
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ABSTRACT: This study was designed to determine the factors that contribute to interindividual variation in the antiplatelet effects of aspirin. We measured platelet response to aspirin in 745 (400 men and 345 women) drug-naive asymptomatic subjects of the Heredity and Phenotype Intervention (HAPI) Heart Study. Whole blood platelet aggregometry was performed to assess response to arachidonic acid, adenosine diphosphate, and collagen at baseline and after 14 days of aspirin 81 mg/day. There was wide interindividual variation in platelet aggregation in response to aspirin, with no clear biological threshold to define aspirin resistance. Variation in platelet function before and after aspirin was heritable. Women exhibited greater platelet aggregability in response to adenosine diphosphate and collagen at baseline and after aspirin administration. The degree to which aspirin inhibited collagen-induced platelet aggregation was also significantly less in women compared with men (mean +/- SD percent inhibition of collagen-induced [1 microg/ml] platelet aggregation 49.9 +/- 30.9 vs 57.5 +/- 42.5 in women and men, respectively, p = 0.005). Using a cutoff <70% inhibition of collagen-induced platelet aggregation, 21% of the total population demonstrated aspirin resistance, which occurred in 30% of women and 16% of men (p = 0.0002). Aspirin-resistant subjects were older, had significantly higher total cholesterol and low-density lipoprotein cholesterol levels, lower hematocrit, and higher platelet count compared with aspirin-sensitive subjects. In conclusion, in this study group, platelet function is heritable. There is wide interindividual variation in platelet response to aspirin as defined by whole blood platelet aggregometry, with women having lower mean percent inhibition of platelet aggregation and greater prevalence of aspirin resistance than men.
The American journal of cardiology 08/2009; 104(4):606-12. · 3.58 Impact Factor
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ABSTRACT: Postprandial triglyceridemia is an emerging risk factor for cardiovascular disease. However, most of the genes that influence postprandial triglyceridemia are not known. We evaluated whether a common nonsynonymous SNP rs1260326/P446L in the glucokinase regulatory protein (GCKR) gene influenced variation in the postprandial lipid response after a high-fat challenge in seven hundred and seventy participants in the Amish HAPI Heart Study who underwent an oral high-fat challenge and had blood samples taken in the fasting state and during the postprandial phase at 1, 2, 3, 4, and 6 h. We found that the minor T allele at rs1260326 was associated with significantly higher fasting TG levels after adjusting for age, sex, and family structure (P (a) = 0.06 for additive model, and P (r) = 0.0003 for recessive model). During the fat challenge, the T allele was associated with significantly higher maximum TG level (P (a) = 0.006), incremental maximum TG level (P (a) = 0.006), TG area under the curve (P (a) = 0.02) and incremental TG area under the curve (P (a) = 0.03). Our data indicate that the rs1260326 T allele of GCKR is associated with both higher fasting levels of TG as well as the postprandial TG response, which may result in higher atherogenic risk.
Human Genetics 07/2009; 126(4):567-74. · 5.07 Impact Factor
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Ying Wang,
Jeffrey R O'Connell,
Patrick F McArdle,
James B Wade,
Sarah E Dorff,
Sanjiv J Shah,
Xiaolian Shi,
Lin Pan,
Evadnie Rampersaud, Haiqing Shen, [......],
Nanette I Steinle,
Afshin Parsa,
Carole C Ober,
Paul A Welling,
Aravinda Chakravarti,
Alan B Weder,
Richard S Cooper,
Braxton D Mitchell,
Alan R Shuldiner,
Yen-Pei C Chang
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ABSTRACT: Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n = 7,125, P < 10(-6)). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cell-based functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na(+) excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.
Proceedings of the National Academy of Sciences 01/2009; 106(1):226-31. · 9.68 Impact Factor
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Toni I Pollin,
Coleen M Damcott, Haiqing Shen,
Sandra H Ott,
John Shelton,
Richard B Horenstein,
Wendy Post,
John C McLenithan,
Lawrence F Bielak,
Patricia A Peyser,
Braxton D Mitchell,
Michael Miller,
Jeffrey R O'Connell,
Alan R Shuldiner
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ABSTRACT: Apolipoprotein C-III (apoC-III) inhibits triglyceride hydrolysis and has been implicated in coronary artery disease. Through a genome-wide association study, we have found that about 5% of the Lancaster Amish are heterozygous carriers of a null mutation (R19X) in the gene encoding apoC-III (APOC3) and, as a result, express half the amount of apoC-III present in noncarriers. Mutation carriers compared with noncarriers had lower fasting and postprandial serum triglycerides, higher levels of HDL-cholesterol and lower levels of LDL-cholesterol. Subclinical atherosclerosis, as measured by coronary artery calcification, was less common in carriers than noncarriers, which suggests that lifelong deficiency of apoC-III has a cardioprotective effect.
Science 01/2009; 322(5908):1702-5. · 31.20 Impact Factor
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ABSTRACT: Capsinoids from the Capsicum genus of plants are nonpungent capsaicin-related substances with effects on metabolism and body weight in animals.
Our objectives were to explore the safety and efficacy of capsinoids taken orally (6 mg/d) for weight loss, fat loss, and change in metabolism and to examine whether candidate genes are predictors of capsinoid response.
This was a 12-wk, placebo-controlled, double-blind, randomized study. Eligibility criteria included a body mass index (BMI; in kg/m(2)) of 25-35. Body weight was measured, and dual-energy X-ray absorptiometry, indirect calorimetry (men only), and genotyping were conducted.
Forty women and 40 men with a mean (+/- SD) age of 42 +/- 8 y and BMI of 30.4 +/- 2.4 were randomly assigned to a capsinoid or placebo group. Capsinoids were well tolerated. Mean (+/- SD) weight change was 0.9 +/- 3.1 and 0.5 +/- 2.4 kg in the capsinoid and placebo groups, respectively (P = 0.86). There was no significant group difference in total change in adiposity, but abdominal adiposity decreased more (P = 0.049) in the capsinoid group (-1.11 +/- 1.83%) than in the placebo group (-0.18 +/- 1.94%), and this change correlated with the change in body weight (r = 0.46, P < 0.0001). Changes in resting energy expenditure did not differ significantly between groups, but fat oxidation was higher at the end of the study in the capsinoid group (least-squares mean difference: 21.0 mg/min; P = 0.06). Of 13 genetic variants tested, TRPV1 Val585Ile and UCP2 -866 G/A correlated significantly with change in abdominal adiposity.
Treatment with 6 mg/d capsinoids orally appeared to be safe and was associated with abdominal fat loss. Capsinoid ingestion was associated with an increase in fat oxidation that was nearly significant. We identified 2 common genetic variants that may be predictors of therapeutic response.
American Journal of Clinical Nutrition 01/2009; 89(1):45-50. · 6.67 Impact Factor
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Evadnie Rampersaud,
Lawrence F Bielak,
Afshin Parsa, Haiqing Shen,
Wendy Post,
Kathleen A Ryan,
Patrick Donnelly,
John A Rumberger,
Patrick F Sheedy,
Patricia A Peyser,
Alan R Shuldiner,
Braxton D Mitchell
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ABSTRACT: Coronary artery calcification (CAC) and common carotid artery intima-media thickness (CIMT) are measures of subclinical vascular disease. This 2000-2006 study aimed to characterize the associations among coronary artery disease risk factors, CAC quantity, and CIMT and to estimate shared genetic and environmental contributions to both CAC and CIMT among 478 asymptomatic Amish adults in Lancaster County, Pennsylvania. Heritability for CAC quantity and CIMT, adjusted for age and sex, was 0.42 (P = 0.0001) and 0.29 (P = 0.003), respectively. CAC quantity and CIMT were modestly correlated (adjusted r = 0.14, P = 0.003) but showed little evidence of shared genetic or environmental factors. However, significant genetic correlations were found for CAC quantity and total cholesterol (0.44 (standard error, 0.19); P = 0.03), for CAC quantity and low density lipoprotein cholesterol (0.55 (standard error, 0.17); P = 0.005), and for CIMT and waist circumference (0.58 (standard error, 0.25); P = 0.046), suggesting shared genes for these risk factors and measures of subclinical disease. Results suggest that some of the same genes influence variation in CAC and low density lipoprotein cholesterol, whereas a different set of genes influences variation in CIMT and waist circumference.
American journal of epidemiology 10/2008; 168(9):1016-23. · 5.59 Impact Factor
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Evadnie Rampersaud,
Braxton D Mitchell,
Toni I Pollin,
Mao Fu, Haiqing Shen,
Jeffery R O'Connell,
Julie L Ducharme,
Scott Hines,
Paul Sack,
Rosalie Naglieri,
Alan R Shuldiner,
Soren Snitker
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ABSTRACT: Common FTO (fat mass and obesity associated) gene variants have recently been associated with body mass index (BMI) and obesity in several large studies. The role of lifestyle factors (such as physical activity) in those with an underlying FTO genetic predisposition is unknown.
To determine if FTO variants are associated with BMI in Old Order Amish (OOA) individuals, and to further determine whether the detrimental associations of FTO gene variants can be lessened by increased physical activity, a total of 704 healthy OOA adults were selected from the Heredity and Phenotype Intervention (HAPI) Heart Study, an investigation of gene x environment interactions in cardiovascular disease, for whom objective quantified physical activity measurements were available and for whom 92 single-nucleotide polymorphisms (SNPs) in FTO were genotyped.
Twenty-six FTO SNPs were associated with BMI (P = .04 to <.001), including rs1477196 (P < .001) and rs1861868 (P < .001), 2 SNPs in moderate linkage disequilibrium in the OOA (D' = 0.82; r(2) = 0.36). Stratified analyses of rs1861868 revealed its association with BMI to be restricted entirely to those subjects with low sex- and age-adjusted physical activity scores (P < .001); in contrast, the SNP had no effect on those with above-average physical activity scores (P = .29), with the genotype x physical activity interaction achieving statistical significance (P = .01). Similar evidence for interaction was also obtained for rs1477196.
Our results strongly suggest that the increased risk of obesity owing to genetic susceptibility by FTO variants can be blunted through physical activity. These findings emphasize the important role of physical activity in public health efforts to combat obesity, particularly in genetically susceptible individuals.
Archives of internal medicine 09/2008; 168(16):1791-7. · 11.46 Impact Factor
