TY - JOUR
T1 - Whole-genome association study identifies STK39 as a hypertension susceptibility gene
AU - Wang, Ying
AU - O'Connell, Jeffrey R.
AU - McArdle, Patrick F.
AU - Wade, James B.
AU - Dorff, Sarah E.
AU - Shah, Sanjiv J.
AU - Shi, Xiaolian
AU - Pan, Lin
AU - Rampersaud, Evadnie
AU - Shen, Haiqing
AU - Kim, James D.
AU - Subramanya, Arohan R.
AU - Steinle, Nanette I.
AU - Parsa, Afshin
AU - Ober, Carole C.
AU - Welling, Paul A.
AU - Chakravarti, Aravinda
AU - Weder, Alan B.
AU - Cooper, Richard S.
AU - Mitchell, Braxton D.
AU - Shuldiner, Alan R.
AU - Chang, Yen Pei C.
PY - 2009/1/6
Y1 - 2009/1/6
N2 - 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.
AB - 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.
KW - Blood pressure
KW - Essential hypertension
KW - Genome-wide association study
KW - SPAK
KW - STK39
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U2 - 10.1073/pnas.0808358106
DO - 10.1073/pnas.0808358106
M3 - Article
C2 - 19114657
AN - SCOPUS:58549108489
SN - 0027-8424
VL - 106
SP - 226
EP - 231
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -