Resistant Hypertension Variants Link to Hyperaldosteronism and Potassium Levels

BACKGROUND: We aimed to characterize the genetic architecture of resistant hypertension (rHTN), which affects up to 18% of hypertensive individuals and increases cardiovascular disease risk. METHODS: We conducted a genome-wide association study on rHTN, defined as use of 3 or more concomitant antihypertensive drugs for at least 6 months without reaching blood pressure target (in the 3-drug case), comparing it to controlled hypertension (cHTN), in which persons on 1 or 2 antihypertensives for at least 6 months reach target BP after 30 days of therapy initiation. The study included 23 508 rHTN cases and 24 393 cHTN controls, identified through drug prescription and blood pressure data from Iceland (deCODE), the UK (UK Biobank), and the US (eMERGE). Further analyses included comparisons with all hypertensive individuals (diagnosed with International Classification of Diseases, Tenth Revision code I10) and normotensives (no hypertension diagnosis). RESULTS: We found 24 rHTN variants, 17 of which used published BP variants as prior. Fifteen risk-increasing rHTN alleles are associated with lower serum potassium and increased hyperaldosteronism risk. Individuals with rHTN and cHTN had lower potassium levels before drug therapy than normotensives. All antihypertensive drug classes increased potassium levels in cHTN, while only aldosterone antagonists increased levels in rHTN. Mendelian randomization analysis was consistent with rHTN being a manifestation of hyperaldosteronism. The variant conferring the largest effect on both rHTN and hyperaldosteronism is a stop-gain variant in ENPEP in the aldosterone pathway. CONCLUSIONS: We discovered sequence variants that have different effects on rHTN and cHTN. Our study indicates that genetically determined hyperaldosteronism may be largely accountable for rHTN.