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The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN.

ABSTRACT: Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); responses to anti-hypertensive drugs vary across race groups. To examine potential interactions between the use of loop diuretics and HTN traits, we analyzed systolic (SBP) and diastolic (DBP) blood BP from 1222 AA and 1231 EA participants in the Hypertension Genetic Epidemiology Network (HyperGEN). Population-specific score tests were used to test associations of SBP and DBP, using a panel of genotyped and imputed single nucleotide polymorphisms (SNPs) for AA (2.9 million SNPs) and EA (2.3 million SNPs). Several promising loci were identified through gene-loop diuretic interactions, although no SNP reached genome-wide significance after adjustment for genomic inflation. In AA, SNPs in or near the genes NUDT12, CHL1, GRIA1, CACNB2, and PYHIN1 were identified for SBP, and SNPs near ID3 were identified for DBP. For EA, promising SNPs for SBP were identified in ESR1 and for DBP in SPATS2L and EYA2. Among these SNPs, none were common across phenotypes or population groups. Biologic plausibility exists for many of the identified genes, suggesting that these are candidate genes for regulation of BP and/or anti-hypertensive drug response. The lack of genome-wide significance is understandable in this small study employing gene-drug interactions. These findings provide a set of prioritized SNPs/candidate genes for future studies in HTN. Studies in more diversified population samples may help identify previously missed variants.

SUBMITTER: de Las Fuentes L

PROVIDER: S-EPMC3872290 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN.

de las Fuentes Lisa L Sung Yun Ju YJ Schwander Karen L KL Kalathiveetil Sonia S Hunt Steven C SC Arnett Donna K DK Rao D C DC

Frontiers in genetics 20131225

Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); ...[more]

PMID: 24400021

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Project description:BACKGROUND:Despite the fact that loop diuretics are a landmark in acute heart failure (AHF) treatment, few trials exist that evaluate whether the duration and timing of their administration and drug amount affect outcome. In this study, we sought to evaluate different loop diuretic infusion doses in relation to outcome and to diuretic response (DR), which was serially measured during hospitalization. METHODS:This is a post-hoc analysis of a DIUR-HF trial. We divided our sample on the basis of intravenous diuretic dose during hospitalization. Patients taking less than 125 mg of intravenous furosemide (median value) were included in the low dose group (LD), patients with a diuretic amount above this threshold were inserted in the high dose group (HD). The DR formula was defined as weight loss/40 mg daily of furosemide and it was measured during the first 24 h, 72 h, and over the whole infusion period. Outcome was considered as death due to cardiovascular causes or heart failure hospitalization. RESULTS:One hundred and twenty-one AHF patients with reduced ejection fractions (EF) were evaluated. The cardiovascular (CV) death/heart failure (HF) re-hospitalization rate was significantly higher in the HD group compared to the LD group (75% vs. 22%; p < 0.001). Both low DR, measured during the entire infusion period (HR 3.25 (CI: 1.92-5.50); p < 0.001) and the intravenous diuretic HD (HR 5.43 [CI: 2.82-10.45]; p < 0.001) were related to outcome occurrence. Multivariable analysis showed that DR (HR 3.01 (1.36-6.65); p = 0.006), intravenous diuretic HD (HR 2.83 (1.24-6.42); p=0.01) and worsening renal function (WRF) (HR 2.21 (1.14-4.28); p = 0.01) were related to poor prognosis. CONCLUSIONS:HD intravenous loop diuretic administration is associated with poor prognosis and less DR. Low DR measured during the whole intravenous administration better predicts outcome compared to DR measured in the early phases. ClinicalTrials.gov Acronym and Identifier Number: DIUR-HF; NCT01441245; registered on 23 September 2011.

Dataset Information

The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN.

Publications

The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN.

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