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1.  Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study 
Aging Cell  2014;14(1):49-59.
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.
PMCID: PMC4324456  PMID: 25476875
apolipoprotein E; age; DNA methylation; variants; epidemiology; interaction
2.  The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study 
Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed.
PMCID: PMC4165277  PMID: 25278896
AGT gene; antihypertensive drugs; hypertension; coronary heart disease; heart failure
3.  The SCARB1 gene is associated with lipid response to dietary and pharmacological interventions 
Journal of human genetics  2008;53(8):10.1007/s10038-008-0302-2.
The scavenger receptor class B type 1 (SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggested that the SCARB1 gene may contribute to variation in plasma lipid levels at the fasting; however, the results have been inconsistent and it is unclear if SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with post-fenofibrate change for triglyceride (TG) (P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response as well as response to fenofibrate intervention.
PMCID: PMC3836273  PMID: 18542840
Scavenger receptor class B type 1; lipid; genetics; fenofibrate; postprandial
4.  Sex-Specific Associations Between Screen Time and Lipoprotein Subfractions 
Time spent in sedentary activities (such as watching television) has previously been associated with several risk factors for cardiovascular disease (CVD) such as increased low-density lipoprotein cholesterol (LDL-C). Little is known about associations with lipoprotein subfractions. Using television and computer screen time in hours per day as a measure of sedentary time, we examined the association of screen time with lipoprotein subfractions.
Data were used from men and women forming the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study population. Mixed linear models specified lipoprotein measures as the outcome, and screen time as the predictor for fourteen lipoprotein subfraction measures, and included age, smoking status, pedigree, and fat, carbohydrate daily alcohol and energy intake as covariates. Analyses were run separately for men (n = 623) and women (n = 671). A step-down Bonferroni correction was applied to results. The analysis was repeated for significant results (p < .05), additionally controlling for body mass index (BMI) and moderate and vigorous physical activity.
Linear models indicated that screen time was associated with five lipoprotein parameters in women: the concentration of large VLDL particles (p = .01), LDL particle number (p = .01), concentration of small LDL particles (p = .04), the concentration of large HDL particles (p = .04), and HDL diameter (p = .02). All associations remained after controlling for moderate or vigorous physical activity and BMI.
We show that sedentary time is associated with lipoprotein measures, markers of cardiometabolic disease, independently of physical activity and BMI, in women but not men.
PMCID: PMC4251454  PMID: 23980250
sedentary time; diet; fat intake; lipoprotein size; BMI; exercise; television
5.  Association of Low-Grade Albuminuria with Adverse Cardiac Mechanics: Findings from the HyperGEN Study 
Circulation  2013;129(1):42-50.
Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear, but may be due to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction.
Methods and Results
In the HyperGEN study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (N=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively), and early diastolic (e′) tissue velocities. We used E/e′ ratio as a marker of increased LV filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were African-American. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with GLS, GCS, GRS, e′ velocity, and E/e′ ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute GLS (multivariable-adjusted mean GLS [95% CI] for UACR Quartile 1 = 15.3 [15.0–15.5]% vs. UACR Q4 = 14.6 [14.3–14.9]%, P for trend <0.001) and increased E/e′ ratio (Q1 = 25.3 [23.5–27.1] vs. Q4 = 29.0 [27.0–31.0], P= 0.003). The association between UACR and GLS was present even in participants with UACR < 30 mg/g (P<0.001 after multivariable adjustment).
Albuminuria, even at low levels, is associated with adverse cardiac mechanics and higher E/e′ ratio.
PMCID: PMC3888488  PMID: 24077169
albuminuria; cardiac mechanics; strain; echocardiography
6.  Hemodynamic and Echocardiographic Profiles in African American Compared With White Offspring of Hypertensive Parents: The HyperGEN Study 
Alterations in cardiovascular structure and function have been shown to precede the finding of elevated blood pressure.
This study is part of the Hypertension Genetic Epidemiologic Network (HyperGEN) in which genetic and environmental determinants of hypertension were investigated in 5 geographical field centers. All nonhypertensive offspring (n = 1,035) were included from the entire HyperGEN study population that consists of 2,225 hypertensive patients and 1,380 nonhypertensive patients who had adequate echocardiographic left ventricular (LV) mass measurements. Participants were compared by self-declared race (African American and white).
Nonhypertensive African American offspring were younger (aged 31 years vs. 38 years), more likely to be female, and had a higher body mass index (BMI) and higher systolic blood pressure (SBP) than their white counterparts. After adjusting for age, sex, SBP, pulse pressure (PP), BMI, diabetes status, and family effects, we observed statistically significant and potentially pathophysiological differences (all with P ≤ 0.001) with greater LV mass/height, relative wall thickness, and posterior wall thickness and with lesser midwall shortening, PP/stroke volume, and (PP/stroke volume)/fat-free body mass.
This study shows that ethnic differences in hemodynamic and echocardiographic profiles exist in a large, population-based cohort of nonhypertensive offspring of hypertensive parents.
PMCID: PMC3848631  PMID: 24242823
blood pressure; echocardiography hypertensive offspring; HyperGEN; hypertension; left ventricular mass.
7.  Adult Height and Prevalence of Coronary Artery Calcium: The NHLBI Family Heart Study 
Adult height has been hypothesized to be inversely associated with coronary heart disease but studies have produced conflicting results. We sought to examine the relationship between adult height and the prevalence of coronary artery calcium (CAC), a direct measure of subclinical atherosclerosis and surrogate marker of CHD.
Method and Results
We evaluated the relationship between adult height and CAC in 2,703 participants from the NHLBI Family Heart Study who underwent cardiac computed tomography. We used generalized estimating equations to calculate the prevalence odds ratios for the presence of CAC (CAC>0) across sex-specific quartiles of height. The mean age of the sample was 54.8 years and 60.2% were female. There was an inverse association between adult height and CAC. After adjusting for age, race, field center, waist circumference, smoking, alcohol, physical activity, systolic blood pressure, antihypertensive medications, diabetes, diabetic medications, LDL cholesterol, HDL cholesterol, lipid-lowering medications, and income, individuals in the tallest quartile had 30% lower odds of having prevalent CAC. The odds ratios (95% CI) for the presence of CAC across consecutive sex-specific quartiles of height were 1.0 (reference), 1.15 (0.86–1.53), 0.95(0.73–1.22), and 0.70 (0.53–0.93), p for trend <0.01. There was no evidence of effect modification for the relationship between adult height and CAC by age or socioeconomic status.
The results of our study suggest an inverse, independent association between adult height and CAC.
PMCID: PMC3970195  PMID: 24336983
risk factor; imaging; epidemiology
8.  Genetic loci associated with circulating levels of very long-chain saturated fatty acids[S] 
Journal of Lipid Research  2015;56(1):176-184.
Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10−13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10−40) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10−26) and lignoceric acid (P = 3.20 × 10−21). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
PMCID: PMC4274065  PMID: 25378659
arachidic acid; behenic acid; lignoceric acid; sphingolipids
9.  Divided States of America: Regional Variation in Cardiovascular Health 
PMCID: PMC3540676  PMID: 23316334
editorials; disparities; health status; heart; regional variation
10.  Association of dietary omega-3 fatty acids with prevalence of metabolic syndrome: The National Heart, Lung, and Blood Institute Family Heart Study 
Clinical nutrition (Edinburgh, Scotland)  2013;32(6):10.1016/j.clnu.2013.05.002.
Background & Aims
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. Omega-3 fatty acids have been relatively well studied in relation to many individual cardiovascular risk factors; however, their effects on MetS are not well established.
We conducted a cross-sectional study consisting of 4,941 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study to assess the relation of dietary omega-3 fatty acids with the prevalence of MetS. Omega-3 intake was assessed using a food frequency questionnaire and we used generalized estimating equations to estimate adjusted odds ratios for prevalent MetS.
Our study population had a mean age (SD) of 52.1 (13.9) years and 45.9% were men. The mean (SD) of dietary omega-3 fatty acids was 0.25g/day (0.27). From the lowest to the highest quintile of dietary omega-3 fatty acids, multivariable adjusted ORs (95% CI) for MetS were 1.00 (ref), 0.90 (0.72–1.13), 1.03 (0.82–1.28), 0.94 (0.74–1.18), and 0.99 (0.77–1.25), respectively. In a secondary analysis, neither fish consumption nor dietary alpha-linolenic acid was associated with MetS.
Our findings do not support an association between dietary omega-3 fatty acids and MetS in a large US population.
PMCID: PMC3791144  PMID: 23711994
Omega-3 fatty acids; fish; dietary alpha-linolenic acid (ALA); metabolic syndrome
11.  Genetic variation in NCAM1 contributes to left ventricular wall thickness in hypertensive families 
Circulation Research  2011;108(3):279-283.
Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals.
Identify genetic predictors of echocardiographic phenotypes in hypertensive families.
Methods & Results
A multi-stage genome-wide association study (GWAS) was conducted in hypertensive-ascertained African American families (HyperGEN, Stage I; GENOA, Stage II); findings were replicated in HyperGEN Caucasian families (Stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. In Stages I and II, 1258 and 989 African Americans, and Stage III 1316 Caucasians, were analyzed using mixed models adjusted for ancestry. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior (PWT) and intraventricular septum (IVST)), and relative wall thickness (RWT). In Stage I, 5 single nucleotide polymorphisms (SNP) had P≤10−6. In Stage II, one SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In Stage III, rs1436109 was associated with RWT (P=5.47×10−4) and LVID (P=1.86×10−4). Fisher’s combined P-value for all stages was RWT=3.80×10−9, PWT=3.12×10−7, IVST=8.69×10−7, LV mass=2.52×10−3, and LVID=4.80×10−4.
This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt-sensitive rats. Our initial screening in hypertensive African-Americans may have provided the context for this novel locus.
PMCID: PMC3328104  PMID: 21212386
GWAS; NCAM1; hypertrophy; genomics
12.  Biomarkers of inflammation and hemostasis associated with left ventricular mass: The Multiethnic Study of Atherosclerosis (MESA) 
Biomarkers of inflammation and hemostasis have been associated with left ventricular (LV) mass. We studied relationships of C-reactive protein (CRP), interleukin-6 (IL6), D-dimer, soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor 1 (PAI-1), soluble thrombomodulin (sTM), soluble tumor necrosis factor type 1 receptor (sTNFR1), von Willebrand factor (vWF), soluble E-selectin (sE-selectin), factor VIII, fibrinogen, matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 9 (MMP9) with LV mass in an asymptomatic population. Multi-Ethnic Study of Atherosclerosis participants underwent magnetic resonance imaging to characterize LV mass; biomarkers were measured using standardized protocols (N = 763 to 4979). Adjusted models were used to associate each biomarker with LV mass while correcting for potential confounding.
LV mass was associated with many biomarkers after adjustment for demographic characteristics and traditional cardiovascular risk factors. Although the demographic and risk factor adjustments attenuated the association of CRP and IL6 with LV mass, further adjustment for weight changed regression coefficients from positive to negative for CRP and IL6 for LV mass. sTM, Factor VIII, and vWF were directly associated with LV mass in fully-adjusted models. For sTNFR1, sICAM-1, D-dimer, fibrinogen, and PAI-1, adjustment for risk factors and weight rendered associations with LV mass nonsignificant.
In this large cohort free of clinical cardiovascular disease, several hemostasis and inflammation markers were associated with LV mass. The unusual finding of a negative relationship of CRP and IL6 with LV mass only after adjustment for weight suggests that the effects of inflammation on LV mass are strongly influenced by obesity.
PMCID: PMC3243453  PMID: 22200000
Left ventricle; biomarker; hemostasis; inflammation
13.  Diastolic wall strain: a simple marker of abnormal cardiac mechanics 
Cardiovascular Ultrasound  2014;12(1):40.
Diastolic wall strain (DWS), defined using posterior wall thickness (PWT) measurements from standard echocardiographic images (DWS = [PWT(systole)-PWT(diastole)]/PWT(systole)), has been proposed as a marker of left ventricular (LV) diastolic stiffness. However, the equation for DWS is closely related to systolic radial strain, and whether DWS is associated with abnormal cardiac mechanics (reduced systolic strains and diastolic tissue velocities) is unknown. We sought to determine the relationship between DWS and systolic and diastolic cardiac mechanics.
We calculated DWS and performed speckle-tracking analysis in a large population- and family-based study (Hypertension Genetic Epidemiology Network [HyperGEN]; N = 1907 after excluding patients with ejection fraction [EF] < 50% or posterior wall motion abnormalities). We measured global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively) and early diastolic (e’) tissue velocities, and we determined the independent association of DWS with cardiac mechanics using linear mixed effects models to account for relatedness among study participants. We also prospectively performed receiver-operating characteristic (ROC) analysis of DWS for the detection of abnormal cardiac mechanics in a separate, prospective validation study (N = 35).
In HyperGEN (age 51 ± 14 years, 59% female, 45% African-American, 57% hypertensive), mean DWS was 0.38 ± 0.05. DWS decreased with increasing comorbidity burden (β-coefficient -0.013 [95% CI -0.015, -0.011]; P < 0.0001). DWS was independently associated with GLS, GCS, GRS, and e’ velocity (adjusted P < 0.05) but not LV chamber compliance (EDV20, P = 0.97). On prospective speckle-tracking analysis, DWS correlated well with GLS, GCS, and GRS (R = 0.61, 0.57, and 0.73, respectively; P < 0.001 for all comparisons). C-statistics for DWS as a diagnostic test for abnormal GLS, GCS, and GRS were: 0.78, 0.79, and 0.84, respectively.
DWS, a simple parameter than can be calculated from routine 2D echocardiography, is closely associated with systolic strain parameters and early diastolic (e’) tissue velocities but not LV chamber compliance.
PMCID: PMC4197332  PMID: 25277882
Strain; Speckle-tracking; Echocardiography; Cardiac mechanics; Diastolic dysfunction; Systolic dysfunction
14.  Stroke Genetics Network (SiGN) Study: Design and rationale for a genome-wide association study of ischemic stroke subtypes 
Background and Purpose
Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The NINDS Stroke Genetics Network (SiGN) contributes substantially to meta-analyses that focus on specific subtypes of stroke.
The NINDS Stroke Genetics Network (SiGN) includes ischemic stroke cases from 24 Genetic Research Centers (GRCs), 13 from the US and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating GRCs. Through the Center for Inherited Diseases Research (CIDR), SiGN plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide SNP arrays, and add to these another 4,253 previously genotyped cases for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. CIDR-generated genotypes and corresponding phenotypic data will be shared with the scientific community through dbGaP, and brain MRI studies will be centrally archived.
The SiGN consortium, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
PMCID: PMC4056331  PMID: 24021684
ischemic stroke; genetics; genomics
15.  RNA Expression Profiling of Human iPSC-Derived Cardiomyocytes in a Cardiac Hypertrophy Model 
PLoS ONE  2014;9(9):e108051.
Cardiac hypertrophy is an independent risk factor for cardiovascular disease and heart failure. There is increasing evidence that microRNAs (miRNAs) play an important role in the regulation of messenger RNA (mRNA) and the pathogenesis of various cardiovascular diseases. However, the ability to comprehensively study cardiac hypertrophy on a gene regulatory level is impacted by the limited availability of human cardiomyocytes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer the opportunity for disease modeling. Here we utilize a previously established in vitro model of cardiac hypertrophy to interrogate the regulatory mechanism associated with the cardiac disease process. We perform miRNA sequencing and mRNA expression analysis on endothelin 1 (ET-1) stimulated hiPSC-CMs to describe associated RNA expression profiles. MicroRNA sequencing revealed over 250 known and 34 predicted novel miRNAs to be differentially expressed between ET-1 stimulated and unstimulated control hiPSC-CMs. Messenger RNA expression analysis identified 731 probe sets with significant differential expression. Computational target prediction on significant differentially expressed miRNAs and mRNAs identified nearly 2000 target pairs. A principal component analysis approach comparing the in vitro data with human myocardial biopsies detected overlapping expression changes between the in vitro samples and myocardial biopsies with Left Ventricular Hypertrophy. These results provide further insights into the complex RNA regulatory mechanism associated with cardiac hypertrophy.
PMCID: PMC4177883  PMID: 25255322
16.  Genome-wide interaction of genotype by erythrocyte n-3 fatty acids contributes to phenotypic variance of diabetes-related traits 
BMC Genomics  2014;15(1):781.
Little is known about the interplay between n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level. The present study aimed to examine variance contributions of genotype by environment (GxE) interactions for different erythrocyte n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level in a non-Hispanic white population living in the U.S.A. (n = 820). A tool for Genome-wide Complex Trait Analysis (GCTA) was used to estimate the genome-wide GxE variance contribution of four diabetes-related traits: HOMA-Insulin Resistance (HOMA-IR), fasting plasma insulin, glucose and adiponectin. A GxE genome-wide association study (GWAS) was conducted to further elucidate the GCTA results. Replication was conducted in the participants of the Boston Puerto Rican Health Study (BPRHS) without diabetes (n = 716).
In GOLDN, docosapentaenoic acid (DPA) contributed the most significant GxE variance to the total phenotypic variance of both HOMA-IR (26.5%, P-nominal = 0.034) and fasting insulin (24.3%, P-nominal = 0.042). The ratio of arachidonic acid to eicosapentaenoic acid + docosahexaenoic acid contributed the most significant GxE variance to the total variance of fasting glucose (27.0%, P-nominal = 0.023). GxE variance of the arachidonic acid/eicosapentaenoic acid ratio showed a marginally significant contribution to the adiponectin variance (16.0%, P-nominal = 0.058). None of the GCTA results were significant after Bonferroni correction (P < 0.001). For each trait, the GxE GWAS identified a far larger number of significant single-nucleotide polymorphisms (P-interaction ≤ 10E-5) for the significant E factor (significant GxE variance contributor) than a control E factor (non-significant GxE variance contributor). In the BPRHS, DPA contributed a marginally significant GxE variance to the phenotypic variance of HOMA-IR (12.9%, P-nominal = 0.068) and fasting insulin (18.0%, P-nominal = 0.033).
Erythrocyte n-3 fatty acids contributed a significant GxE variance to diabetes-related traits at the genome-wide level.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-781) contains supplementary material, which is available to authorized users.
PMCID: PMC4168207  PMID: 25213455
17.  Modulation by Dietary Fat and Carbohydrate of IRS1 Association With Type 2 Diabetes Traits in Two Populations of Different Ancestries 
Diabetes Care  2013;36(9):2621-2627.
Insulin receptor substrate 1 (IRS1) is central to insulin signaling pathways. This study aimed to examine the association of IRS1 variants with insulin resistance (IR) and related phenotypes, as well as potential modification by diet.
Two IRS1 variants (rs7578326 and rs2943641) identified by genome-wide association studies as related to type 2 diabetes were tested for their associations with IR and related traits and interaction with diet in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820) and the Boston Puerto Rican Health Study (BPRHS) (n = 844).
Meta-analysis indicated that rs7578326 G-allele carriers and rs2943641 T-allele carriers had a lower risk of IR, type 2 diabetes, and metabolic syndrome (MetS). Significant interactions on IR and MetS were found for these two variants and their haplotypes with diet. In GOLDN, rs7578326 G-allele carriers and rs2943641 T-allele carriers and their haplotype G-T carriers had a significantly lower risk of IR and MetS than noncarriers only when the dietary saturated fatty acid-to-carbohydrate ratio was low (≤0.24). In both GOLDN (P = 0.0008) and BPRHS (P = 0.011), rs7578326 G-allele carriers had a lower risk of MetS than noncarriers only when dietary monounsaturated fatty acids were lower than the median intake of each population.
IRS1 variants are associated with IR and related traits and are modulated by diet in two populations of different ancestries. These findings suggest that IRS1 variants have important functions in various metabolic disorders and that dietary factors could modify these associations.
PMCID: PMC3747864  PMID: 23596181
18.  Genetic Risk Scores Associated with Baseline Lipoprotein Subfraction Concentrations Do Not Associate with Their Responses to Fenofibrate 
Biology  2014;3(3):536-550.
Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels.
PMCID: PMC4192626  PMID: 25157911
pharmacogenetics; candidate gene study; lipoprotein; fenofibrate; NMR; GOLDN; genetic risk score; particle size; LDL size; HDL size
Journal of hypertension  2009;27(8):1585-1593.
To identify genes contributing to variation in echocardiographic left ventricular (LV) mass and related traits using linkage and linkage disequilibrium analysis in sibships ascertained on hypertension.
The HyperGEN Study of LV hypertrophy characterized LV mass, relative wall thickness (RWT), and aortic root diameter (ARD) with echocardiograms collected using a standardized protocol at four HyperGEN field centers. A high-throughput scanning fluorescence detector system genotyped 387 polymorphisms distributed throughout the genome. Linkage analyses were conducted once genotyping results became available for 885 siblings from 382 sibships.
Although single LOD score peaks ≥ 1.2 were found on chromosomes 1, 4, 5, 6, 7, 8, 9, 10, 12, 14, 17, and 21, we observed a broad band of peaks in both ethnic groups (white and black) on chromosome 4 and selected candidate genes (NPY1R, NPY2R, NPY5R, SFPR2, CPE, IL15, EDNRA) from this region. Using cases and controls from extremes of the LV mass index, RWT, and ARD distributions, we assessed associations with these phenotypes and haplotype-tagging single nucleotide polymorphisms (SNPs) in the candidates. Among blacks, SNPs in IL15, NPY2R, and NPY5R showed strong evidence for association (p < 0.005); all candidates except EDNRA showed suggestive association (p < 0.05). In whites, NPY2R, NPY5R, and SFRP2 SNPs offered suggestive evidence of association with one or more traits (p < 0.05).
Genetic variation in NPY1R, NPY2R, NPY5R, CPE, IL15, and SFRP2, detected using linkage analysis in hypertensive siblings, was associated with LV phenotypes in blacks and/or whites.
PMCID: PMC2868312  PMID: 19593212
left ventricular hypertrophy; genetics; echocardiography
20.  Chocolate consumption and prevalence of metabolic syndrome in the NHLBI Family Heart Study 
e-SPEN journal  2012;7(4):e139-e143.
Background & aims
Previous studies have suggested that cocoa products, which are rich sources of flavonoids, may lower blood pressure, serum cholesterol, fasting blood glucose and improve endothelial function. However, it is unclear whether consumption of cocoa products including chocolate influences the risk of metabolic syndrome (MetS).
In a cross-sectional design, we sought to examine the association between chocolate consumption and the prevalence of MetS.
We studied 4098 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study aged 25–93 years. Chocolate consumption was assessed using a semi-quantitative food-frequency questionnaire. MetS was defined using the NCEP III criteria. Generalized estimating equations were used to estimate prevalence odds ratios of MetS according to frequency of chocolate intake.
Of the 4098 participants (mean age 51.7 y) included in the analyses, 2206 (53.8%) were female. The prevalence of metabolic syndrome in our population was 30.2%. Compared with those who did not consume any chocolate, multivariate adjusted odds ratios (95% CI) for MetS were 1.26 (0.94, 1.69), 1.15 (0.85, 1.55), and 0.99 (0.66, 1.51) among women who reported chocolate consumption of 1–3 times/ month, 1–4 times/week, and 5+ times/week, respectively. Corresponding values for men were: 1.13 (0.82, 1.57), 1.02 (0.74, 1.39), and 1.21 (0.79, 1.85).
These data do not support an association between chocolate intake and the prevalence of MetS in US adult men and women.
PMCID: PMC4130386  PMID: 25126517
Chocolate; Metabolic syndrome; Cardiovascular disease risk
21.  Adducin 1 (alpha) Gly460Trp variant is associated with left ventricular geometry in Caucasians and African Americans: The HyperGEN Study 
Normal left ventricular (LV) mass and geometry is required for optimal LV functioning. Abnormalities in either result in increased morbidity and mortality. The adducing 1 (alpha) gene (ADD1) Gly460Trp polymorphism has been associated with high blood pressure and increased plasma volume, both predictors of LV mass and function. In this cross-sectional study, we evaluate the association between this polymorphism and LV mass and geometry. LV mass, relative wall thickness (RWT), and systolic and diastolic parameters were measured using echocardiography in 3483 African American and Caucasian subjects from the Hypertension Genetic Epidemiology Network (HyperGEN). Analysis of covariance was used to estimate the polymorphism's association with echocardiograph parameters, stratified by race. The model was adjusted for age, diastolic and systolic blood pressure, glomerular filtration rate, smoking, low and high density lipoprotein cholesterol, urinary sodium, and body mass index. In Caucasians, the Trp allele was associated with higher ejection fraction (EF) (P = .02), fractional shortening (FS) (P = .02), and RWT (P = .03). In African Americans, the Trp allele was negatively associated with RWT (P = .02), but no association was found with EF (P= .08) or FS (P= .09). The polymorphism was not associated with diastolic function parameters in either racial group. We found no association of ADD1 Gly460Trp with LV mass in Caucasians or African Americans; however, it was associated with unfavorable LV geometry (higher RWT) in Caucasians and favorable LV geometry (lower RWT) in African Americans after controlling for factors that would affect plasma volume.
PMCID: PMC3076776  PMID: 21532846
Adducin; genetic polymorphism; left ventricular mass; left ventricular geometry; hypertrophy
22.  SNPs located at CpG sites modulate genome-epigenome interaction 
Epigenetics  2013;8(8):802-806.
DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P-value < 10−9), and meSNPs account for over two thirds of the strongest meQTL signals (P-value < 10−200). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes.
PMCID: PMC3883783  PMID: 23811543
DNA methylation; meSNP; meQTL; epigenome-wide study; Infinium Human Methylation 450K BeadChip
23.  Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial 
The pharmacogenomics journal  2013;14(1):48-53.
Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.
PMCID: PMC3701736  PMID: 23545897
Methotrexate; rheumatoid arthritis; pharmacogenetics
24.  Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval 
The pharmacogenomics journal  2013;14(1):6-13.
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%), and QT prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-SNP interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0×10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
PMCID: PMC3766418  PMID: 23459443
QT interval; pharmacogenomics; gene-environment interaction
25.  Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response 
Human genetics  2014;133(7):919-930.
Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.
PMCID: PMC4112746  PMID: 24604477

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