Salt sensitivity of blood pressure and aldosterone: interaction between Lysine-specific demethylase 1 gene, sex, and age.

CONTEXT: Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular risk, especially in individuals of African descent, although underlying mechanisms remain obscure. Lysine-specific demethylase 1 (LSD1) is a salt-sensitive epigenetic regulator associated with SSBP and aldosterone dysfunction. An LSD1 risk allele in humans is associated with SSBP and lower aldosterone levels in hypertensive African but not European descent. Heterozygous knockout LSD1 mice display SSBP and aldosterone dysregulation, but this effect is modified by age and biological sex. This might explain differences in cardiovascular risk with aging and biological sex in humans.

OBJECTIVE: To determine if LSD1 risk allele (rs587618) carriers of African descent display a sex-by-age interaction with SSBP and aldosterone regulation.

METHODS: We analyzed 297 individuals of African and European descent from the HyperPATH cohort. We performed multiple regression analyses for outcome variables related to SSBP and aldosterone.

RESULTS: LSD1 risk allele carriers of African (but not European) descent had greater SSBP than non-risk homozygotes. Female LSD1 risk allele carriers of African descent had greater SSBP, mainly relationship-driven by women of low estrogen (postmenopausal). There was a significant LSD1 genotype-sex interaction in aldosterone response to angiotensin II stimulation in individuals ≤50 years, with female carriers displaying decreased aldosterone responsiveness.

CONCLUSIONS: SSBP associated with LSD1 risk allele status is driven by women of deplete estrogen state. Mechanisms related to a resistance to develop SSBP in females are uncertain but may relate to an estrogen modulating effect on mineralocorticoid receptor activation and/or LSD1 epigenetic regulation of the mineralocorticoid receptor.