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 journalArticle

226 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)226-231
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number1
DOIs
StatePublished - Jan 6 2009

Fingerprint

Amish
Genome-Wide Association Study
Hypertension
Alleles
Genes
Blood Pressure
Protein-Serine-Threonine Kinases
Nephrons
Single Nucleotide Polymorphism
Meta-Analysis
Cations
Chlorides
Proteins
Phosphotransferases
Public Health
Mutation

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Whole-genome association study identifies STK39 as a hypertension susceptibility gene. / Wang, Ying; O'Connell, Jeffrey R.; McArdle, Patrick F.; Wade, James B.; Dorff, Sarah E.; Shah, Sanjiv J.; Shi, Xiaolian; Pan, Lin; Rampersaud, Evadnie; Shen, Haiqing; Kim, James D.; Subramanya, Arohan R.; Steinle, Nanette I.; Parsa, Afshin; Ober, Carole C.; Welling, Paul A.; Chakravarti, Aravinda; Weder, Alan B.; Cooper, Richard S.; Mitchell, Braxton D.; Shuldiner, Alan R.; Chang, Yen Pei C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 1, 06.01.2009, p. 226-231.

Research output: Contribution to journalArticle

Wang, Y, O'Connell, JR, McArdle, PF, Wade, JB, Dorff, SE, Shah, SJ, Shi, X, Pan, L, Rampersaud, E, Shen, H, Kim, JD, Subramanya, AR, Steinle, NI, Parsa, A, Ober, CC, Welling, PA, Chakravarti, A, Weder, AB, Cooper, RS, Mitchell, BD, Shuldiner, AR & Chang, YPC 2009, 'Whole-genome association study identifies STK39 as a hypertension susceptibility gene', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 1, pp. 226-231. https://doi.org/10.1073/pnas.0808358106
Wang, Ying ; O'Connell, Jeffrey R. ; McArdle, Patrick F. ; Wade, James B. ; Dorff, Sarah E. ; Shah, Sanjiv J. ; Shi, Xiaolian ; Pan, Lin ; Rampersaud, Evadnie ; Shen, Haiqing ; Kim, James D. ; Subramanya, Arohan R. ; Steinle, Nanette I. ; Parsa, Afshin ; Ober, Carole C. ; Welling, Paul A. ; Chakravarti, Aravinda ; Weder, Alan B. ; Cooper, Richard S. ; Mitchell, Braxton D. ; Shuldiner, Alan R. ; Chang, Yen Pei C. / Whole-genome association study identifies STK39 as a hypertension susceptibility gene. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 1. pp. 226-231.
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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

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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.

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