title: Effects of rare and common blood pressure gene variants on essential hypertension: results from the Family Blood Pressure Program, CLUE, and Atherosclerosis Risk in Communities studies.
abstract: BACKGROUND
  Hypertension affects ≈30% of adults in industrialized countries and is the major risk factor for cardiovascular disease.
  
  
  OBJECTIVE
  We sought to study the genetic effect of coding and conserved noncoding variants in syndromic hypertension genes on systolic blood pressure (BP) and diastolic BP to assess their overall impact on essential hypertension.
  
  
  RESULTS
  We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1, and WNK4) in 560 European American (EA) and African American ancestry GenNet participants with extreme systolic BP. We investigated genetic associations of 2535 variants with BP in 19997 EAs and in 6069 African Americans in 3 types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9747 EA and 3207 African American Atherosclerosis Risk in Communities subjects. Finally, we genotyped 37 missense and common noncoding variants in 6591 EAs and in 6521 individuals (3659 EA/2862 African American) from the CLUE and Family Blood Pressure Program studies, respectively. None of the variants individually reached significant false-discovery rates ≤0.05 for systolic BP and diastolic BP. However, on pooling all coding and noncoding variants, we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G, and WNK1) with higher association at evolutionary conserved sites.
  
  
  CONCLUSIONS
  Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units), and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Khanh-Dung H
authors.initials: KD
authors.lastname: Nguyen
authors.forename: Vasyl
authors.initials: V
authors.lastname: Pihur
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.forename: Ankit
authors.initials: A
authors.lastname: Rakha
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Joe
authors.initials: J
authors.lastname: Coresh
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D001741:Black or African American / Q000235:genetics; D001213:Asian / Q000235:genetics; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D054555:National Heart, Lung, and Blood Institute (U.S.); D011159:Population Surveillance / Q000379:methods*; D011446:Prospective Studies; D012111:Residence Characteristics; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics