Donna K Arnett

University of Alabama at Birmingham, Birmingham, Alabama, United States

Are you Donna K Arnett?

Claim your profile

Publications (495)2738.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cost-effective identification of novel pharmacogenetic variants remains a pressing need in the field. Using data from the Genetics of Lipid Lowering Drugs and Diet Network, we identified genomic regions of relevance to fenofibrate response in a sample of 173 families. Our approach included a multipoint linkage scan, followed by selection of the families showing evidence of linkage. We identified a strong signal for changes in LDL-cholesterol (LDL-C) on chromosome 7 (peak logarithm of odds score=4.76) in the full sample (n=821). The signal for LDL-C response remained even after adjusting for baseline LDL-C. Restricting analyses only to the families contributing to the linkage signal for LDL-C (N=19), we observed a peak logarithm of odds score of 5.17 for chromosome 7. Two genes under this peak (ABCB4 and CD36) were of biological interest. These results suggest that linked family analyses might be a useful approach to gene discovery in the presence of a complex (e.g. multigenic) phenotype.
    Pharmacogenetics and Genomics 07/2015; DOI:10.1097/FPC.0000000000000162 · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To conduct an epigenome-wide analysis of DNA methylation and obesity traits. DNA methylation was quantified in CD4+ T-cells using the Illumina Infinium HumanMethylation450 array in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. Methylation at individual cytosine-phosphate-guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T-cell purity, smoking, and family structure, was modeled. Epigenome-wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n = 2,377) and the Atherosclerosis Risk in Communities study (n = 2,097), were found. Top findings were in CPT1A (meta-analysis P = 2.7 × 10(-43) for BMI and 9.9 × 10(-23) for WC), PHGDH (meta-analysis P = 2.0 × 10(-15) for BMI and 4.0 × 10(-9) for WC), CD38 (meta-analysis P = 6.3 × 10(-11) for BMI and 1.6 × 10(-12) for WC), and long intergenic non-coding RNA 00263 (meta-analysis P = 2.2 × 10(-16) for BMI and 8.9 × 10(-14) for WC), regions with biologically plausible relationships to adiposity. This large-scale epigenome-wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications. © 2015 The Obesity Society.
    Obesity 07/2015; 23(7):1493-501. DOI:10.1002/oby.21111 · 4.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
    Nature 07/2015; DOI:10.1038/nature14618 · 42.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diurnal variation in blood pressure (BP) is regulated, in part, by an endogenous circadian clock; however, few human studies have identified associations between clock genes and BP. Accounting for environmental temperature may be necessary to correct for seasonal bias. We examined whether environmental temperature on the day of participants' assessment was associated with BP, using adjusted linear regression models in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) (n = 819) and the Boston Puerto Rican Health Study (BPRHS) (n = 1,248) cohorts. We estimated phenotypic variance in BP by 18 clock genes and examined individual single-nucleotide polymorphism (SNP) associations with BP using an additive genetic model, with further consideration of environmental temperature. In GOLDN, each additional 1 °C increase in environmental temperature was associated with 0.18mm Hg lower systolic BP [SBP; β ± SE = -0.18±0.05mm Hg; P = 0.0001] and 0.10mm Hg lower diastolic BP [DBP; -0.10±0.03mm Hg; P = 0.001]. Similar results were seen in the BPRHS for SBP only. Clock genes explained a statistically significant proportion of the variance in SBP [V G/V P ± SE = 0.071±0.03; P = 0.001] in GOLDN, but not in the BPRHS, and we did not observe associations between individual SNPs and BP. Environmental temperature did not influence the identified genetic associations. We identified clock genes that explained a statistically significant proportion of the phenotypic variance in SBP, supporting the importance of the circadian pathway underlying cardiac physiology. Although temperature was associated with BP, it did not affect results with genetic markers in either study. Therefore, it does not appear that temperature measures are necessary for interpreting associations between clock genes and BP. Trials related to this study were registered at as NCT00083369 (Genetic and Environmental Determinants of Triglycerides) and NCT01231958 (Boston Puerto Rican Health Study). © Published by Oxford University Press on behalf of American Journal of Hypertension Ltd 2015. This work is written by (a) US Government employees(s) and is in the public domain in the US.
    American Journal of Hypertension 06/2015; DOI:10.1093/ajh/hpv082 · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor thereby attenuating the differential effect by race. Attenuation likely occurs in both race-groups but may be more pronounced in the less-represented race-group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9 *2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study, and compared predictive ability of race-combined versus race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs. 3.0%, p<0.001), and rs12777823 only among African Americans (12.3% vs. 2.3%, p=0.006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs. 19.9%, p=0.003) compared to African Americans. Race-stratified analysis improved dose prediction in both race groups compared to race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race that may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. Copyright © 2015 American Society of Hematology.
    Blood 05/2015; DOI:10.1182/blood-2015-02-627042 · 10.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2,097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed effects regression models were used to test the association of methylation beta value with concurrent BMI and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole blood DNA from 2,377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the GOLDN Study was followed by testing using adipose tissue DNA from 648 women in the MuTHER cohort. Seventy-six (76) BMI-related probes, 164 WC-related probes, and 8 BMI change-related probes passed the threshold for significance in ARIC (p<1 x 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A, and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen (16) of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling, and other diverse pathways, including LGALS3BP, KDM2B, PBX1, and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity, and analytic approaches. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 05/2015; DOI:10.1093/hmg/ddv161 · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care. © 2015 American Heart Association, Inc.
    Circulation 04/2015; 131(19). DOI:10.1161/CIR.0000000000000211 · 14.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.
    Frontiers in Genetics 04/2015; 6:136. DOI:10.3389/fgene.2015.00136
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular diseases are among the most significant health problems in the United States today, with their major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although GWAS have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans, these variants collectively explain <2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here, we report the results from rare-variant analysis of systolic BP using 94,595 rare and low-frequency variants (minor allele frequency, MAF, <5%) from the Illumina exome array genotyped in 2,045 HyperGEN AAs. In addition to single-variant analysis, 4 gene-level association tests were used for analysis: burden and family-based SKAT tests using MAF cutoffs of 1 and 5%. The gene-based methods often provided lower p values than the single-variant approach. Some consistency was observed across these 4 gene-based analysis options. While neither the gene-based analyses nor the single-variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, 6 of the 16 most promising genes are biologically plausible with physiological connections to BP regulation. © 2015 S. Karger AG, Basel.
    Human Heredity 03/2015; 79(1):20-27. DOI:10.1159/000375373 · 1.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Information on the current burden of stroke in Africa is limited. The aim of this review was to comprehensively examine the current and projected burden of stroke in Africa. We systematically reviewed the available literature (PubMed and AJOL) from January 1960 and June 2014 on stroke in Africa. Percentage change in age-adjusted stroke incidence, mortality and disability-adjusted life years (DALYs) for African countries between 1990 and 2010 were calculated from the Global Burden of Diseases (GBD) model-derived figures. Community-based studies revealed an age-standardised annual stroke incidence rate of up to 316 per 100 000 population, and age-standardised prevalence rates of up to 981 per 100 000. Model-based estimates showed significant mean increases in age-standardised stroke incidence. The peculiar factors responsible for the substantial disparities in incidence velocity, ischaemic stroke proportion, mean age and case fatality compared to high-income countries remain unknown. While the available study data and evidence are limited, the burden of stroke in Africa appears to be increasing.
    03/2015; 26(2 Suppl 1):S27-38. DOI:10.5830/CVJA-2015-038
  • [Show abstract] [Hide abstract]
    ABSTRACT: One in six people worldwide will experience a stroke in his/her lifetime. While people in Africa carry a disproportionately higher burden of poor stroke outcomes, compared to the rest of the world, the exact contribution of genomic factors to this disparity is unknown. Despite noteworthy research into stroke genomics, studies exploring the genetic contribution to stroke among populations of African ancestry in the United States are few. Furthermore, genomics data in populations living in Africa are lacking. The wide genomic variation of African populations offers a unique opportunity to identify genomic variants with causal relationships to stroke across different ethnic groups. The Stroke Investigative Research and Educational Network (SIREN), a component of the Human Health and Heredity in Africa (H3Africa) Consortium, aims to explore genomic and environmental risk factors for stroke in populations of African ancestry in West Africa and the United States. In this article, we review the literature on the genomics of stroke with particular emphasis on populations of African origin.
    03/2015; 26(2 Suppl 1):S39-49. DOI:10.5830/CVJA-2015-039
  • Donna K Arnett
    Circulation Cardiovascular Quality and Outcomes 02/2015; 8(2_suppl_1). DOI:10.1161/CIRCOUTCOMES.115.001757 · 5.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance is a major public health concern in the United States. The effects of Apolipoprotein E (Apo E) polymorphism on MetS are not well established. We conducted a cross-sectional study consisting of 1,551 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. MetS was defined according to the AHA-NHLBI-IDF-WHO Harmonized Criteria. We used generalized estimating equations to estimate adjusted odds ratios for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis. Our study population had a mean age (SD) of 56.5 (11.0) years and 49.7% had MetS. There was no association between the Apo E genotypes and MetS. The multivariable adjusted ORs (95% CI) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62-1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47), and 1.87 (0.91-3.85) for the Ɛ3/Ɛ3, Ɛ2/Ɛ2, Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4, and Ɛ4/Ɛ4 genotypes, respectively. In a secondary analysis, Ɛ2/Ɛ3 genotype was associated with 41% lower prevalence odds of low HDL [multivariable adjusted ORs (95% CI) = 0.59 (0.36-0.95)] compared to Ɛ3/Ɛ3 genotype. Our findings do not support an association between Apo E polymorphism and MetS in a multi-center population based study of predominantly white US men and women. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Diabetes/Metabolism Research and Reviews 02/2015; DOI:10.1002/dmrr.2638 · 3.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health. OBJECTIVE: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers. DESIGN: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts. RESULTS: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (beta = 0.0035, P = 4.90 x 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (beta = 0.0053, P = 1.05 x 10(-6)) and Chinese Americans (beta = 0.0028, P = 0.002) but not African Americans (beta = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: beta = 0.0118, P = 4.05 x 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (beta-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans. CONCLUSIONS: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.
    American Journal of Clinical Nutrition 02/2015; 101(2-2):398-406. DOI:10.3945/ajcn.114.094557 · 6.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). We conducted meta-analyses (N to 11668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein) and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma vs. erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary ALA and linoleic acid for DHA and DPA. Our findings reinforce earlier reports that genetically-based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Molecular Nutrition & Food Research 01/2015; DOI:10.1002/mnfr.201400734 · 4.91 Impact Factor
  • Donna K Arnett
    Journal of the American College of Cardiology 01/2015; 65(1):52-4. DOI:10.1016/j.jacc.2014.10.023 · 15.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: -Admixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African-Americans. -The present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides. The analysis was performed in 1,905 unrelated African-American subjects from the National Heart, Lung and Blood Institute's Family Blood Pressure Program. Regions showing admixture evidence were followed-up with family-based association analysis in 3,556 African-American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age(2), sex, body-mass-index, and genome-wide mean ancestry to minimize the confounding due to population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (LDL-C), 8 (HDL-C), 14 (triglycerides) and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52,939 SNPs were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with HDL-C (2 SNPs), LDL-C (4 SNPs) and triglycerides (5 SNPs). The family data was used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions including genes with known associations for cardiovascular disease. -This study identified regions on chromosomes 7, 8, 14 and 19 and 11 SNPs from the fine-mapping analysis that were associated with HDL-C, LDL-C and triglycerides for further studies of cardiovascular disease in African-Americans.
    Circulation Cardiovascular Genetics 12/2014; 8(1). DOI:10.1161/CIRCGENETICS.114.000481 · 6.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Carotid intima-media thickness (cIMT) is a subclinical measure of atherosclerosis with mounting evidence that higher cIMT confers an increased risk of cardiovascular disease. The ryanodine receptor 3 gene (RYR3) has previously been linked to increased cIMT; however, the causal variants have not yet been localized. Therefore, we sequenced 339 480 bp encompassing 104 exons and 2 kb flanking region of the RYR3 gene in 96 HIV-positive white men from the extremes of the distribution of common cIMT from the Fat Redistribution and Metabolic Changes in HIV infection study (FRAM). We identified 2710 confirmed variants (2414 single-nucleotide polymorphisms (SNPs) and 296 insertion/deletions (indels)), with a mean count of 736 SNPs (ranging from 528 to 1032) and 170 indels (ranging from 128 to 214) distributed in each individual. There were 39 variants in the exons and 15 of these were non-synonymous, of which with only 4 were common variants and the remaining 11 were rare variants, one was a novel SNP. We confirmed that the common variant rs2229116 was significantly associated with cIMT in this design (P<7.9 × 10(-9)), and observed seven other significantly associated SNPs (P<10(-8)). These variants including the private non-synonymous SNPs need to be followed up in a larger sample size and also tested with clinical atherosclerotic outcomes.Journal of Human Genetics advance online publication, 11 December 2014; doi:10.1038/jhg.2014.104.
    Journal of Human Genetics 12/2014; 60(2). DOI:10.1038/jhg.2014.104 · 2.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 12/2014; DOI:10.1016/j.ajhg.2014.11.011 · 10.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = -0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 12/2014; 14(1). DOI:10.1111/acel.12293 · 5.94 Impact Factor

Publication Stats

14k Citations
2,738.34 Total Impact Points


  • 2005–2015
    • University of Alabama at Birmingham
      • Department of Epidemiology
      Birmingham, Alabama, United States
    • University of Oslo
      • Department of Nutrition
      Kristiania (historical), Oslo, Norway
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2014
    • American Heart Association
      Dallas, Texas, United States
  • 1997–2014
    • University of Minnesota Duluth
      • • Laboratory Medicine and Pathology
      • • Department of Family Medicine and Community Health
      Duluth, Minnesota, United States
  • 2006–2013
    • University of Alabama
      Tuscaloosa, Alabama, United States
    • University of Utah
      • School of Medicine
      Salt Lake City, Utah, United States
  • 2012
    • United States Department of Agriculture
      Washington, Washington, D.C., United States
  • 2011
    • Oregon Health and Science University
      • Bone and Mineral Unit
      Portland, OR, United States
  • 2005–2010
    • Weill Cornell Medical College
      • Department of Medicine
      New York, New York, United States
  • 2000–2010
    • Washington University in St. Louis
      • • Division of Biostatistics
      • • Department of Genetics
      San Luis, Missouri, United States
  • 2009
    • Universiteit Utrecht
      • Division of Pharmacoepidemiology and Pharmacotherapy
      Utrecht, Provincie Utrecht, Netherlands
    • University of Minnesota Twin Cities
      • Department of Laboratory Medicine and Pathology
      Minneapolis, MN, United States
  • 2007
    • University of Oxford
      Oxford, England, United Kingdom
  • 2004–2007
    • Cornell University
      Итак, New York, United States
  • 2003–2006
    • Boston University
      • Section of Preventive Medicine and Epidemiology
      Boston, Massachusetts, United States
  • 2002–2005
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2001–2005
    • New York Presbyterian Hospital
      • Department of Pain Medicine
      New York City, New York, United States
  • 1999
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
    • Pennsylvania State University
      University Park, Maryland, United States
  • 1994–1996
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      North Carolina, United States
  • 1991
    • University of South Florida
      • Department of Cardiology
      Tampa, FL, United States