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

Human Molecular Genetics, Apr 2013

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.

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

0 The Author 2013. Published by Oxford University Press. All rights reserved - Received July 13, 2012; Revised November 30, 2012; Accepted December 27, 2012 INTRODUCTION Blood pressure (BP) is a cardinal risk factor for cardiovascular disease (CVD). Systolic BP (SBP) and diastolic (DBP) levels are associated with increased risk of atherosclerotic vascular disease and other cardiovascular causes of death (1). Much of the excess CVD risk imparted by BP elevation can be ameliorated through interventions to decrease BP (2). The identification of novel genes and pathways involved in BP regulation may highlight new ways of reducing BP and CVD risk associated with hypertension. The mean arterial pressure (MAP) and pulse pressure (PP, the difference between SBP and DBP) are single BP components associated with CVD risk (3 5). The latter is an indicator of conduit artery stiffness and is known to increase with age, as aortic elasticity decreases. To date, 50 common genetic variants associated with BP and hypertension have been reported, largely through genome-wide association studies (GWAS), meta-analyses and admixture mapping approaches (6 16). The identification of common variants associated with BP may be enriched through further genecentric approaches (17 19). Accordingly, we tested the hypothesis that candidate gene analysis would identify known and novel associations with SBP, DBP, MAP and PP and would confirm previously reported associations. To further investigate and discover associations with BP, we genotyped approximately 50 000 single-nucleotide polymorphisms (SNPs) on a genecentric array (ITMAT-Broad_CARe [IBC] array, Illumina San Diego, CA, USA) that captures variation in 2100 candidate genes for cardiovascular traits including BP (20) in 61 619 individuals of European ancestry. We identified two novel BP-associated loci, at the candidate genes MDM4 and HRH1 and have validated these associations through in silico replication analysis in a large set of independent samples. Discovery association analyses In the primary discovery meta-analysis, four BP traits were analyzed in 61 619 individuals from 27 cohorts, as described in Table 1. We analyzed SBP, DBP, MAP and PP as continuous traits. Cohort characteristics, including age, sex, BP values and the proportion of individuals treated with BP lowering medications, are provided in Table 1. The details of the cohorts are provided in the Supplementary Material, Table S1 and Supplementary Materials. Association analyses were successfully carried out for up to 48 372 SNPs, and summaries of the quality-control (QC) steps and numbers of SNPs removed at each step are provided in Supplementary Material, Table S2A. Cohort-specific genomic control inflation factors, lGC, did not suggest the presence of inflation (Supplementary Material, Table S3). Meta-analysis quantile quantile plots are shown in Supplementary Material, Fig. S1 and P-values for association for all SNPs are provided in Supplementary Material, Table S4. We identified 22 significant SNP-trait associations with SBP, DBP, MAP and PP at 12 different loci (P , 2.4 1026), including two novel loci near HRH1 and MDM4 for BP traits and one novel SNP-trait association in the SOX6 locus, a region previously described in association with MAP. Replication analyses Replication testing was performed in 65 866 additional individuals, including 43 266 individuals in seven cohorts with genome-wide SNP genotypes imputed to HapMap (Supplementary Material, Table S2B) and 22 600 individuals genotyped on the same IBC chip used for the discovery analyses. Through the joint analysis of SNPs considered relevant during the discovery phase combined with replication data, we identified robust association of 22 SNP-trait associations at 12 independent loci meeting our array-wide significance threshold of P , 2.4 1026: six loci were associated with DBP (MTHFR, MDM4, HFE, SH2B3/ATXN2, CSK, FURIN), nine loci were associated with SBP (MTHFR, HRH1, CYP17A1, LSP1, SOX6, ATP2B1, SH2B3/ATXN2, CSK, FURIN), six loci were associated with MAP (MTHFR, ADRB1, ATP2B1, ATXN2, CSK, FURIN) and one locus associated with PP (CYP17A1). The association findings are summarized in Table 2. We confirmed previously reported BP associations at 10 loci, and identified two novel loci: rs347591 associated with SBP (chromosome 3p25, in an intron of HRH1, P 1.57 1028) (Fig. 1A); rs2169137 associated with DBP (chromosome 1q32, in an intron of MDM4, P 5.91028) (Fig. 1B). We additionally found evidence of association of rs281413 (chromosome 19p13 in an intron of ICAM3) with DBP, in our discovery analysis, although it was not confirmed in the replication analysis (P 3.08 1026 in discovery, P 1.4 1025 in the joint analysis). Finally, one of the SNP-trait associations we identified was novel in our analysis, with the association of rs2014408 with SBP (chromosome 11p15, in an intron of SOX6, P 5.71 10210), whereas previously only association with MAP (...truncated)


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