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Resistant Hypertension Variants Link to Hyperaldosteronism and Potassium Levels.
Vinicius Tragante1,2, Patrick Sulem1, Gudmar Thorleifsson1
1Amgen deCODE genetics, Reykjavik, Iceland (V.T., P.S., G. Thorleifsson, M.L.F., A.M.D., E.F., S.G., G.H.H., A.H., I.J., R.P.K., A.E.L., S.H.L., M.I.M., P.M., A.O., L.S., D.O.A., G.S., G.M., G. Thorgeirsson, U.T., D.F.G., K.S., H.H.).
Hypertension (Dallas, Tex. : 1979)
|July 9, 2026
Summary
Resistant hypertension (rHTN) is linked to genetic variants affecting aldosterone. These variants, particularly in ENPEP, suggest genetically determined hyperaldosteronism underlies rHTN, impacting cardiovascular risk.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Endocrinology
Background:
- Resistant hypertension (rHTN) affects up to 18% of hypertensive individuals, significantly increasing cardiovascular disease risk.
- Characterizing the genetic basis of rHTN is crucial for understanding its pathophysiology and developing targeted therapies.
Purpose of the Study:
- To identify genetic variants associated with resistant hypertension (rHTN).
- To investigate the relationship between identified genetic variants, serum potassium levels, and hyperaldosteronism.
- To explore the role of genetically determined hyperaldosteronism in the development of rHTN.
Main Methods:
- A genome-wide association study (GWAS) was conducted comparing rHTN cases (n=23,508) with controlled hypertension (cHTN) controls (n=24,393).
- Data were sourced from Icelandic (deCODE), UK (UK Biobank), and US (eMERGE) biobanks, utilizing drug prescription and blood pressure records.
- Further analyses included comparisons with all hypertensive individuals and normotensives, alongside Mendelian randomization to assess causality.
Main Results:
- Twenty-four variants associated with rHTN were identified, with 17 building on prior blood pressure (BP) variant data.
- Fifteen risk-increasing rHTN alleles correlated with lower serum potassium and increased risk of hyperaldosteronism.
- Mendelian randomization supported hyperaldosteronism as a cause of rHTN, with an ENPEP variant showing the largest effect on both conditions.
Conclusions:
- Sequence variants influencing rHTN and cHTN differently were discovered.
- Genetically determined hyperaldosteronism is strongly implicated as a primary driver of resistant hypertension.
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