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PLoS One. 2014 Oct 2;9(10):e109155. doi: 10.1371/journal.pone.0109155. eCollection 2014.

Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.

Author information

1
University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
2
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
3
The Framingham Heart Study, Framingham, Massachusetts, United States of America; The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
4
Department of Specialties of Medicine, Geneva University Hospitals, Geneva, Switzerland; Center for Complex Disease Genomics, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
5
Department of Statistics, University of Auckland, Auckland, New Zealand.
6
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
7
University of Texas Health Science Center at Houston, Houston, Texas, United States of America; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
8
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Department of Health Services, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
9
Center for Complex Disease Genomics, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Abstract

BACKGROUND:

Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

METHODS AND RESULTS:

Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

CONCLUSION:

Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.

PMID:
25275628
PMCID:
PMC4183565
DOI:
10.1371/journal.pone.0109155
[Indexed for MEDLINE]
Free PMC Article

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