title: Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes.
abstract: BACKGROUND
  The renin-angiotensin-aldosterone system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood.
  
  
  RESULTS
  We meta-analyzed genome-wide association data for plasma renin activity (n=5275), plasma renin concentrations (n=8014), and circulating aldosterone (n=13289) from ≤4 population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6487). Single-nucleotide polymorphisms (SNPs) in 2 independent loci displayed associations with plasma renin activity at genome-wide significance (P<5×10(-8)). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], P=5.5×10(-8)). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: P=0.001 for plasma renin, P=0.024 for plasma aldosterone concentration; and rs4253311 with P<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911; P=8.81×10(-9)), but did not replicate (P=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in blacks.
  
  
  CONCLUSIONS
  We identified 2 genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.forename: Ervin R
authors.initials: ER
authors.lastname: Fox
authors.forename: Solomon K
authors.initials: SK
authors.lastname: Musani
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Christine
authors.initials: C
authors.lastname: Meisinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schlesinger
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Jöel
authors.initials: J
authors.lastname: Menard
authors.forename: Serge
authors.initials: S
authors.lastname: Hercberg
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rawal
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Anke
authors.initials: A
authors.lastname: Hannemann
authors.forename: Marcus
authors.initials: M
authors.lastname: Dörr
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.forename: Pierre
authors.initials: P
authors.lastname: Meneton
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
mesh_terms: D000450:Aldosterone / Q000097:blood / Q000235:genetics; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000235:genetics; D007704:Kininogens / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011288:Prekallikrein / Q000235:genetics / Q000378:metabolism; D019655:Quantitative Trait, Heritable; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000235:genetics*
chemical_list: C000591034:KNG1 protein, human; D007704:Kininogens; D000450:Aldosterone; D011288:Prekallikrein; D012083:Renin
keywords: aldosterone; genome-wide association study; renin-angiotensin system