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Blood pressure loci identified with a gene-centric array.

ABSTRACT: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

SUBMITTER: Johnson T

PROVIDER: S-EPMC3234370 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Blood pressure loci identified with a gene-centric array.

Johnson Toby T Gaunt Tom R TR Newhouse Stephen J SJ Padmanabhan Sandosh S Tomaszewski Maciej M Kumari Meena M Morris Richard W RW Tzoulaki Ioanna I O'Brien Eoin T ET Poulter Neil R NR Sever Peter P Shields Denis C DC Thom Simon S Wannamethee Sasiwarang G SG Whincup Peter H PH Brown Morris J MJ Connell John M JM Dobson Richard J RJ Howard Philip J PJ Mein Charles A CA Onipinla Abiodun A Shaw-Hawkins Sue S Zhang Yun Y Davey Smith George G Day Ian N M IN Lawlor Debbie A DA Goodall Alison H AH Fowkes F Gerald FG Abecasis Gonçalo R GR Elliott Paul P Gateva Vesela V Braund Peter S PS Burton Paul R PR Nelson Christopher P CP Tobin Martin D MD van der Harst Pim P Glorioso Nicola N Neuvrith Hani H Salvi Erika E Staessen Jan A JA Stucchi Andrea A Devos Nabila N Jeunemaitre Xavier X Plouin Pierre-François PF Tichet Jean J Juhanson Peeter P Org Elin E Putku Margus M Sõber Siim S Veldre Gudrun G Viigimaa Margus M Levinsson Anna A Rosengren Annika A Thelle Dag S DS Hastie Claire E CE Hedner Thomas T Lee Wai K WK Melander Olle O Wahlstrand Björn B Hardy Rebecca R Wong Andrew A Cooper Jackie A JA Palmen Jutta J Chen Li L Stewart Alexandre F R AF Wells George A GA Westra Harm-Jan HJ Wolfs Marcel G M MG Clarke Robert R Franzosi Maria Grazia MG Goel Anuj A Hamsten Anders A Lathrop Mark M Peden John F JF Seedorf Udo U Watkins Hugh H Ouwehand Willem H WH Sambrook Jennifer J Stephens Jonathan J Casas Juan-Pablo JP Drenos Fotios F Holmes Michael V MV Kivimaki Mika M Shah Sonia S Shah Tina T Talmud Philippa J PJ Whittaker John J Wallace Chris C Delles Christian C Laan Maris M Kuh Diana D Humphries Steve E SE Nyberg Fredrik F Cusi Daniele D Roberts Robert R Newton-Cheh Christopher C Franke Lude L Stanton Alice V AV Dominiczak Anna F AF Farrall Martin M Hingorani Aroon D AD Samani Nilesh J NJ Caulfield Mark J MJ Munroe Patricia B PB

American journal of human genetics 20111117 6

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated wit ...[more]

PMID: 22100073

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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.

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Blood pressure loci identified with a gene-centric array.

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Blood pressure loci identified with a gene-centric array.

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