From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene.
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.
Wang
Ying
Y
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
O'Connell
Jeffrey R
JR
McArdle
Patrick F
PF
Wade
James B
JB
Dorff
Sarah E
SE
Shah
Sanjiv J
SJ
Shi
Xiaolian
X
Pan
Lin
L
Rampersaud
Evadnie
E
Shen
Haiqing
H
Kim
James D
JD
Subramanya
Arohan R
AR
Steinle
Nanette I
NI
Parsa
Afshin
A
Ober
Carole C
CC
Welling
Paul A
PA
Chakravarti
Aravinda
A
Weder
Alan B
AB
Cooper
Richard S
RS
Mitchell
Braxton D
BD
Shuldiner
Alan R
AR
Chang
Yen-Pei C
YP
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
D049992:Sodium Chloride Symporters; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human