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Functional splice site variants in AVPR1A protect against idiopathic hyperaldosteronism
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DOI：10.1016/j.gendis.2026.102377.png)
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Abstract
En 中文
Idiopathic hyperaldosteronism (IHA) is a common form of hypertension and increases the risk of cardiovascular events even after the recommended medical therapy. As the pathogenesis of IHA is largely unclear, elucidation of genetic factors may discover novel therapeutic targets. We performed a whole-genome sequencing on blood samples from 261 IHA and 261 age- and sex-matched healthy controls in the cohort of the Chongqing Primary Aldosteronism Study (CONPASS). We observed a strong association between IHA and a rare, heterozygous single-nucleotide splice variant (c.971-2A>C) in the AVPR1A gene that encodes the arginine vasopressin receptor known to mediate adrenal cell proliferation. In vitro, the splice variant largely blocked AVPR1A downstream pathways. AVPR1A overexpression resulted in a > 25-fold upregulation of CYP11B2 gene expression and markedly increased the secretion of aldosterone and its precursors (P < 0.001), whereas overexpression of AVPR1A harboring this splice variant rescued these effects. AVPR1A knockdown significantly suppressed aldosterone biosynthesis, with CYP11B2 expression reduced by 80% (P < 0.001) and aldosterone levels decreased by 50% (P < 0.001). In vivo, AVPR1A overexpression led to significant elevations in both CYP11B2 expression and circulating aldosterone levels (P < 0.05). In conclusion, a pathogenic splice site variation in AVPR1A conferred substantial protection from IHA.
Keywords:
AVPR1A
Idiopathic hyperaldosteronism
Protection
Splice site variation
Whole-genome sequencing
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