Replication of the Wellcome Trust genome-wide association study of essential hypertension: the Family Blood Pressure Program

Abstract

Essential hypertension is a principal cardiovascular risk factor whose origin remains unknown. Classical genetic studies have shown that blood pressure is at least partially heritable, opening a window to understanding the pathophysiology of essential hypertension in the human using modern genetic tools. The Wellcome Trust Case Control Consortium has recently published the results of screening the genomes of 2000 essential hypertension cases and 3000 controls using 500 000 genome-wide single nucleotide polymorphisms (SNPs). None of the variants proved to be genome-wide significant after correction for multiple tests but the most significantly associated SNPs (P<10(-5)) constitute a priority list that warrant follow-up in other studies. We describe here replication studies of the top six SNPs in subjects from the US National Heart, Lung, and Blood Institute funded Family Blood Pressure Program comprising 11 433 individuals recruited by hypertensive families. The results suggest that only one of the six SNPs might be associated with essential hypertension in Americans of European origin. This SNP shows a significant but opposite effect in Americans of Hispanic origin and no association in African Americans. The significance of the opposing effect estimates is unclear. No replication could be shown for hypertension status, but there are differences in study design. This attempted replication highlights that essential hypertension studies will require more comprehensive and larger genetic screens

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor

“…The Family Blood Pressure Program could not replicate any hypertensive associations for the six top-ranking SNPs revealed by Wellcome Trust Case Control Consortium. 31 No doubt, complexity of blood pressure regulation is related to a number of phenomena. They include the possible multiple pleiotropic variants of low penetrance, genetic epistasis, ethnic diversity, phenotypic heterogeneity and uncontrolled environmental factors.…”

Non-synonymous single-nucleotide polymorphisms associated with blood pressure and hypertension

“…3 K Recently several genome-wide association studies have been performed on blood pressure and hypertension to identify the genetic factors. [4][5][6][7][8][9][10][11] What this study adds K This study provides an opportunity to identify causative non-synonymous genetic variations in a hypertension genome-wide association study. K On the basis of previous reports, newly identified genes ADC, PLD2 and BDNF seem to be relevant to hypertension, suggesting the reliability of this approach.…”

Replication of the Wellcome Trust genome-wide association study on essential hypertension in a Korean population

“…Although the FBPP did not reproduce the results of the WTCCC study, one (rs1937506) of the six SNPs was found to be associated with hypertension in Hispanic Americans and European Americans. 5 To explore the genetic basis of prevalent, lifestyle-related complex diseases in Korea, we launched the KARE (Korean Association REsource) project in 2007. Participants (n¼10 038) aged 40-69 years in the Ansung (n¼5018) and Ansan (n¼5020) community-based cohorts were genotyped using the Affymetrix SNP Array 5.0.…”

“…3 To address the genetic risk factors for hypertension, many association studies have been conducted on the basis of casecontrol comparisons, as well as population-based analyses of both candidate genes and the entire genome. [4][5][6][7][8][9] The first genome-wide association study was carried out by the Wellcome Trust Case Control Consortium (WTCCC), which enrolled 2000 hypertensive patients and 3000 normotensive controls. 4 Although no single SNP (single nucleotide polymorphism) achieved genome-wide significance (Po5Â10 -7 ), six variants were found to be highly associated with hypertension (Po10 À5 ).…”