Whole-genome association study identifies STK39 as a hypertension susceptibility gene
Open accessAbstract
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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In some cases, associations between common variants and endophenotypes have been confirmed by in vitro biochemical assays for structural and regulatory effects.
“in some cases these have been confirmed by in vitro biochemical assays for structural and regulatory effects [eg83–85].”
From Rare and common variants: twenty arguments (2012) · cites this paper as [84]
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- Authors
- Wang, Y., O'Connell, J. R., McArdle, P. F., Wade, J. B., Dorff, S. E., Shah, S. J., Shi, X., Pan, L., Rampersaud, E., Shen, H., Kim, J. D., Subramanya, A. R., Steinle, N. I., Parsa, A., Ober, C. C., Welling, P. A., Chakravarti, A., Weder, A. B., Cooper, R. S., Mitchell, B. D., Shuldiner, A. R., & Chang, Y.-P. C.
- Affiliations
- University of Maryland, Baltimore (US)
- Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201;
- University of Chicago (US)
- Georgetown University (US)
- Johns Hopkins University (US)
- University of Michigan (US)
- Loyola Medicine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-01-06
- Volume
- 106
- Issue
- 1
- Pages
- 226-231
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2629209
- OpenAlex
- W2093657574
- Cited by
- 298
- References
- 33
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 3 · 2020: 8 · 2019: 8 · 2018: 12 · 2017: 14 · 2016: 19 · 2015: 15 · 2014: 18 · 2013: 20 · 2012: 31
- FWCI
- 29.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL088120, U01HL084756, U01 HL72515-01, R01HL076768, U01HL072515)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK032839, DK32839, F32DK072865, R01DK054261, R01 DK54261-07)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Keywords
- hypertension, STK39, systolic blood pressure, diastolic blood pressure, serine/threonine kinase, WNK kinases, cation-chloride cotransporters, distal nephron, renal sodium excretion, intronic regulatory elements, allele-specific transcription, Amish, meta-analysis
- MeSH terms
- Blood Pressure, Diastole, Gene Frequency, Humans, Hypertension, Nephrons, Protein Binding, Sodium, Systole, Protein Serine-Threonine Kinases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Sodium Chloride Symporters, Genome-Wide Association Study
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