Regulatory Variant of Klotho (rs9563124) Associates with Ang-II Stimulated Aldosterone and Salt Sensitive Blood Pressure.

CONTEXT: Dysregulated aldosterone responsiveness to angiotensin II (AngII) may contribute to salt-sensitive blood pressure (SSBP), but the genetic basis of dynamic renin-angiotensin-aldosterone system (RAAS) physiology remains unclear. OBJECTIVE: To determine whether common Klotho (KL) variants are associated with baseline aldosterone, AngII-stimulated aldosterone, aldosterone reactivity, and SSBP, and to assess biological plausibility through functional annotation. METHODS: We evaluated 168 KL-region variants in 407 HyperPATH participants studied under controlled dietary sodium conditions. Variants were screened for associations with SSBP and aldosterone phenotypes, and rs9563124 was prioritized based on consistent associations. Age- and sex-stratified analyses were performed, and public expression quantitative trait locus (eQTL) and regulatory annotation resources were used to investigate potential mechanisms. RESULTS: The rs9563124 G allele was associated with higher SSBP (beta=2.853; P=0.00185), baseline aldosterone (beta=0.733; P=0.00156), AngII-stimulated aldosterone (beta=1.949; P=0.00062), and aldosterone reactivity (delta-aldosterone; beta=1.23; P=0.00611). Associations with SSBP were stronger in women and participants aged ≥50 years, whereas associations with aldosterone phenotypes appeared greater in women and participants <50 years; these subgroup findings were exploratory. Functional annotation identified tissue-specific KL eQTLs and allele-specific transcription factor motif alterations, supporting a regulatory role. CONCLUSIONS: KL variation, represented by rs9563124, was associated with aldosterone phenotypes and salt-sensitive blood pressure. Functional annotation supports a regulatory mechanism linking KL variation to endocrine responsiveness. Independent replication and experimental validation are needed to establish causality and clinical relevance.