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

doi:10.1073/pnas.0808358106

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

^aDivision of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201;
^bDepartment of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201;
^cSection of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60611;
^dDepartment of Human Genetics, University of Chicago, Chicago, IL 60637;
^eGeorgetown University School of Medicine, Washington, DC 20057;
^fDivision of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201;
^gMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
^hDepartment of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48106; and
ⁱDepartment of Preventive Medicine and Epidemiology, Loyola Stritch School of Medicine, Maywood, IL 60153

Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 11, 2008 (received for review August 27, 2008)

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.

Footnotes

¹To whom correspondence should be addressed. E-mail: cchang{at}medicine.umaryland.edu
Author contributions: Y.W., A.C., A.B.W., B.D.M., A.R. Shuldiner, and Y.-P.C.C. designed research; Y.W., J.B.W., S.E.D., S.J.S., N.I.S., C.C.O., and Y.-P.C.C. performed research; J.R.O., C.C.O., A.B.W., R.S.C., and A.R. Shuldiner contributed new reagents/analytic tools; Y.W., J.R.O., P.F.M., S.J.S., X.S., L.P., E.R., H.S., J.D.K., A.R. Subramanya, A.P., C.C.O., P.A.W., A.C., B.D.M., and Y.-P.C.C. analyzed data; and Y.W., J.B.W., A.R. Shuldiner, and Y.-P.C.C. wrote the paper.
The authors declare no conflicts of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0808358106/DCSupplemental.