Association between circulating Klotho levels and hypertension: insights from NHANES, Mendelian randomization, and an Asian cohort.

BACKGROUND: Klotho has been implicated in blood pressure regulation through its effects on vascular integrity, calcium-phosphate homeostasis, and oxidative stress pathways. However, population-level data exploring its association with hypertension remain inconclusive. METHODS: Data from the U.S. National Health and Nutrition Examination Survey (NHANES; 2007-2016) were analyzed using weighted multivariate generalized linear regression models. Klotho levels were evaluated as both continuous and categorical (quartiles) variables. A nonlinear dose-response relationship was further explored using spline regression. To assess potential causality, a two-sample Mendelian randomization (MR) analysis was conducted using the inverse-variance weighted (IVW) method. External validation was performed in an independent Asian cohort. RESULTS: In NHANES, no statistically significant association was observed between serum Klotho and hypertension, either as a continuous variable or by quartiles after adjusting for coronary heart disease (CHD) or hyperlipidemia (e.g. Q4: OR = 0.89 [95% CI: 0.79-1.00], p = 0.06 for CHD adjustment). However, nonlinear analysis revealed a potential inflection point at 1342.8 pg/mL, suggesting a threshold-dependent relationship. The MR analysis yielded no evidence of a causal association between genetically predicted Klotho levels and hypertension risk (IVW OR = 1.005 [95% CI: 0.999-1.011], p = 0.09). Findings from the small Asian cohort were consistent with null associations (OR = 0.999 [95% CI: 0.991-1.007], p = 0.80). CONCLUSION: Across three distinct populations, no robust linear or causal relationship between Klotho levels and hypertension was identified. However, due to the limited sample size of the Asian cohort, future studies are warranted to validate these findings in larger populations.