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Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study.

ABSTRACT: Blood pressure (BP) variability has a genetic component, most of which has yet to be attributed to specific variants. One promising strategy for gene discovery is analysis of interactions between single-nucleotide polymorphisms (SNPs) and BP-related factors, including age, sex, and body mass index (BMI). Educational attainment, a marker for socioeconomic status, has effects on both BP and BMI.We investigated SNP-education interaction effects on BP in genome-wide data on 3,836 subjects in families from the Framingham Heart Study. The ABEL suite was used to adjust for age, sex, BMI, medication use, and kinship and to perform 1 degree-of-freedrom (df) and 2 df SNP-education interaction tests.An SNP in PTN was associated with increased systolic BP (5.4mm Hg per minor allele) in those without a bachelor's degree but decreased systolic BP (1.6mm Hg per allele) in those with a bachelor's degree (2 df; P = 2.08 × 10(-8)). An SNP in TOX2 was associated with increased diastolic BP (DBP; 4.1mm Hg per minor allele) in those with no more educational attainment than high school but decreased DBP in those with education past high school (-0.7; 1 df; P = 3.74 × 10(-8)). Three suggestive associations were also found: in MYO16 (pulse pressure: 2 df; P = 2.89 × 10(-7)), in HAS2 (DBP: 1 df; P = 1.41 × 10(-7)), and in DLEU2 (DBP: 2 df; P = 1.93 × 10(-7)). All 5 genes are related to BP, including roles in vasodilation and angiogenesis for PTN and TOX2.PTN and TOX2 are associated with BP. Analyzing SNP-education interactions may detect novel associations. Education may be a surrogate for unmeasured exposures and behaviors modifying SNP effects on BP.

SUBMITTER: Basson J

PROVIDER: S-EPMC3915746 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study.

Basson Jacob J Sung Yun Ju YJ Schwander Karen K Kume Rezart R Simino Jeannette J de las Fuentes Lisa L Rao Dabeeru D

American journal of hypertension 20140128 3

<h4>Background</h4>Blood pressure (BP) variability has a genetic component, most of which has yet to be attributed to specific variants. One promising strategy for gene discovery is analysis of interactions between single-nucleotide polymorphisms (SNPs) and BP-related factors, including age, sex, and body mass index (BMI). Educational attainment, a marker for socioeconomic status, has effects on both BP and BMI.<h4>Methods</h4>We investigated SNP-education interaction effects on BP in genome-wid ...[more]

PMID: 24473254

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Project description:Alcohol consumption is a known risk factor for hypertension, with recent candidate studies implicating gene-alcohol interactions in blood pressure (BP) regulation. We used 6882 (predominantly) Caucasian participants aged 20-80 years from the Framingham SNP Health Association Resource (SHARe) to perform a genome-wide analysis of SNP-alcohol interactions on BP traits. We used a two-step approach in the ABEL suite to examine genetic interactions with three alcohol measures (ounces of alcohol consumed per week, drinks consumed per week, and the number of days drinking alcohol per week) on four BP traits [systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure]. In the first step, we fit a linear mixed model of each BP trait onto age, sex, BMI, and antihypertensive medication while accounting for the phenotypic correlation among relatives. In the second step, we conducted 1 degree-of-freedom (df) score tests of the SNP main effect, alcohol main effect, and SNP-alcohol interaction using the maximum likelihood estimates (MLE) of the parameters from the first step. We then calculated the joint 2 df score test of the SNP main effect and SNP-alcohol interaction using MixABEL. The effect of SNP rs10826334 (near SLC16A9) on SBP was significantly modulated by both the number of alcoholic drinks and the ounces of alcohol consumed per week (p-values of 1.27E-08 and 3.92E-08, respectively). Each copy of the G-allele decreased SBP by 3.79 mmHg in those consuming 14 drinks per week vs. a 0.461 mmHg decrease in non-drinkers. Index SNPs in 20 other loci exhibited suggestive (p-value ≤ 1E-06) associations with BP traits by the 1 df interaction test or joint 2 df test, including 3 rare variants, one low-frequency variant, and SNPs near/in genes ESRRG, FAM179A, CRIPT-SOCS5, KAT2B, ADCY2, GLI3, ZNF716, SLIT1, PDE3A, KERA-LUM, RNF219-AS1, CLEC3A, FBXO15, and IGSF5. SNP-alcohol interactions may enhance discovery of novel variants with large effects that can be targeted with lifestyle modifications.

Project description:About one quarter of adults are hypertensive and high blood pressure carries increased risk for heart disease, stroke, kidney disease and death. Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions.In Framingham Heart Study families, we analyzed genome-wide SNP (Affymetrix 100K GeneChip) associations with systolic (SBP) and diastolic (DBP) BP at a single examination in 1971-1975 (n = 1260), at a recent examination in 1998-2001 (n = 1233), and long-term averaged SBP and DBP from 1971-2001 (n = 1327, mean age 52 years, 54% women) and with arterial stiffness measured by arterial tonometry (carotid-femoral and carotid-brachial pulse wave velocity, forward and reflected pressure wave amplitude, and mean arterial pressure; 1998-2001, n = 644). In primary analyses we used generalized estimating equations in models for an additive genetic effect to test associations between SNPs and phenotypes of interest using multivariable-adjusted residuals. A total of 70,987 autosomal SNPs with minor allele frequency > or = 0.10, genotype call rate > or = 0.80, and Hardy-Weinberg equilibrium p > or = 0.001 were analyzed. We also tested for association of 69 SNPs in six renin-angiotensin-aldosterone pathway genes with BP and arterial stiffness phenotypes as part of a candidate gene search.In the primary analyses, none of the associations attained genome-wide significance. For the six BP phenotypes, seven SNPs yielded p values < 10(-5). The lowest p-values for SBP and DBP respectively were rs10493340 (p = 1.7 x 10(-6)) and rs1963982 (p = 3.3 x 10(-6)). For the five tonometry phenotypes, five SNPs had p values < 10(-5); lowest p-values were for reflected wave (rs6063312, p = 2.1 x 10(-6)) and carotid-brachial pulse wave velocity (rs770189, p = 2.5 x 10(-6)) in MEF2C, a regulator of cardiac morphogenesis. We found only weak association of SNPs in the renin-angiotensin-aldosterone pathway with BP or arterial stiffness.These results of genome-wide association testing for blood pressure and arterial stiffness phenotypes in an unselected community-based sample of adults may aid in the identification of the genetic basis of hypertension and arterial disease, help identify high risk individuals, and guide novel therapies for hypertension. Additional studies are needed to replicate any associations identified in these analyses.

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Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study.

Publications

Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study.

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