Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Ying Wang, Jeffrey R. O'Connell, Patrick F. McArdle, James B. Wade, Sarah E. Dorff, Sanjiv J. Shah, Xiaolian Shi, Lin Pan, Evadnie Rampersaud, Haiqing Shen, James D. Kim, Arohan R. Subramanya, Nanette I. Steinle, Afshin Parsa, Carole C. Ober, Paul A. Welling, Aravinda Chakravarti, Alan B. Weder, Richard S. Cooper, Braxton D. MitchellAlan R. Shuldiner, Yen Pei C Chang

Research output: Contribution to journalArticlepeer-review

254 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)226-231
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - Jan 6 2009


  • Blood pressure
  • Essential hypertension
  • Genome-wide association study
  • SPAK
  • STK39

ASJC Scopus subject areas

  • General


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