title: 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.
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).
  
  
  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.
  
  
  CONCLUSIONS
  Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
authors.affiliation: University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: 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.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: 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.
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.affiliation: Department of Statistics, University of Auckland, Auckland, New Zealand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 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.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Center for Complex Disease Genomics, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
mesh_terms: D000375:Aging / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics*; D015331:Cohort Studies; D006321:Heart / Q000502:physiology*; D006801:Humans; D017421:Sequence Analysis