Loci influencing blood pressure identified using a cardiovascular gene-centric array

Abstract

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

“…These observations are further emphasised by a recent large-scale study genotyping approximately 50 000 SNPs in approximately 2100 genes, which revealed significant correlations between mRNA expression and the MDM4 SNP rs2169137 which is in linkage disequilibrium with rs4245739 SNP (Ganesh et al 2013).…”

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

“…Crucially, a genomic region containing ATP2B1, which encodes for PMCA1, has been identified as having a very strong association with BP variance and/or with hypertensive disease in different human population groups (Cho et al, 2009;Levy et al, 2009;Hong et al, 2010;Takeuchi et al, 2010;Johnson et al, 2011). Importantly, SNPs associating ATP2B1 with BP have attained genome wide significance in replication analyses in multiple different ethnic groups and have shown a consistently high level of genetic association (Tabara et al, 2010;Miyaki et al, 2012;Xi et al, 2012;Ganesh et al, 2013;Wang et al, 2013). SNPs relating to ATP2B1 in a Japanese cohort were found to give an odds ratio of 1.17 to 1.31 for hypertension (Tabara et al, 2010), a very similar level of risk as reported by other large scale GWAS.…”

An update on genome-wide association studies of hypertension

“…The largest GWAS effort to date involving participants of African origin was done by the Continental Origins and Genetic Epidemiology Network (COGENT) (Franceschini et al 2013). Discovery samples were obtained from 19 studies with an aggregate sample size of 29,000 individuals.…”