Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array

Siim Sõber(University of Tartu), Elin Org(University of Tartu), Katrin Kepp(University of Tartu), Peeter Juhanson(University of Tartu), S. Eyheramendy(Pontificia Universidad Católica de Chile), Christian Gieger(Helmholtz Zentrum München), Peter Lichtner(Helmholtz Zentrum München), Norman Klopp(Helmholtz Zentrum München), Gudrun Veldre(University of Tartu), Margus Viigimaa(North Estonia Medical Centre), Angela Döring(Helmholtz Zentrum München), for the Kooperative Gesundheitsforschung in der Region Augsburg study(University of Tartu), Margus Putku(University of Tartu), Piret Kelgo(William Harvey Research Institute), for the HYPertension in ESTonia study(William Harvey Research Institute), Sue Shaw‐Hawkins(William Harvey Research Institute), Philip Howard(William Harvey Research Institute), Abiodun Onipinla(William Harvey Research Institute), Richard Dobson(University of Cambridge), Stephen Newhouse(William Harvey Research Institute), Morris J. Brown(University of Cambridge), Anna F. Dominiczak(University of Leicester), John Connell(Centre for Human Genetics), Nilesh J. Samani(University of Leicester), Martin Farrall(Centre for Human Genetics), for the MRC British Genetics of Hypertension study(Helmholtz Zentrum München), Mark J. Caulfield(Helmholtz Zentrum München), Patricia B. Munroe(TUM Klinikum), Thomas Illig(Helmholtz Zentrum München), H.‐Erich Wichmann(Helmholtz Zentrum München), Thomas Meitinger(TUM Klinikum), Maris Laan(University of Tartu)
PLoS ONE
June 26, 2009
10.1371/journal.pone.0006034
Cited by 115Open Access
Full Text

Abstract

The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region+/-10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10(-3)) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

Related Papers

No related papers found

Powered by citation graph analysis