title: From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene.
abstract: Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n = 7,125, P < 10(-6)). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cell-based functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na(+) excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Patrick F
authors.initials: PF
authors.lastname: McArdle
authors.forename: James B
authors.initials: JB
authors.lastname: Wade
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dorff
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Xiaolian
authors.initials: X
authors.lastname: Shi
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Evadnie
authors.initials: E
authors.lastname: Rampersaud
authors.forename: Haiqing
authors.initials: H
authors.lastname: Shen
authors.forename: James D
authors.initials: JD
authors.lastname: Kim
authors.forename: Arohan R
authors.initials: AR
authors.lastname: Subramanya
authors.forename: Nanette I
authors.initials: NI
authors.lastname: Steinle
authors.forename: Afshin
authors.initials: A
authors.lastname: Parsa
authors.forename: Carole C
authors.initials: CC
authors.lastname: Ober
authors.forename: Paul A
authors.initials: PA
authors.lastname: Welling
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Alan B
authors.initials: AB
authors.lastname: Weder
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Yen-Pei C
authors.initials: YP
authors.lastname: Chang
mesh_terms: D001794:Blood Pressure / Q000235:genetics; D003971:Diastole; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics*; D009399:Nephrons / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics*; D012964:Sodium / Q000652:urine; D049992:Sodium Chloride Symporters; D013599:Systole; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: D049992:Sodium Chloride Symporters; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human