Key result
The LSD1 risk allele (rs587618) was associated with greater salt sensitivity of blood pressure in individuals of African descent, driven primarily by women in a low-estrogen state.
Why the study?
Salt sensitivity of blood pressure increases cardiovascular risk, especially in individuals of African descent, but underlying mechanisms and whether an LSD1 risk allele interacts with sex and age remain unclear.
Does LSD1 risk allele (rs587618) carrier status increase salt sensitivity of blood pressure and alter aldosterone regulation in individuals of African descent?
Cohort (n=297)
Does LSD1 risk allele (rs587618) carrier status increase salt sensitivity of blood pressure and alter aldosterone regulation in individuals of African descent?
The LSD1 risk allele increases salt sensitivity of blood pressure in women of African descent, particularly in postmenopausal states, highlighting a gene-sex-age interaction in hypertension risk.
No change to BP management in African descent patients; leaves open gene-sex interactions in salt-sensitive hypertension.
CONTEXT: Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular risk, especially in individuals of African descent, although the 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 individuals of 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: This work aims 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 nonrisk homozygotes. Female LSD1 risk allele carriers of African descent had greater SSBP, mainly relationship-driven by women with low estrogen (postmenopausal). There was a statistically significant LSD1 genotype-sex interaction in aldosterone response to angiotensin II stimulation in individuals aged 50 years or younger, with female carriers displaying decreased aldosterone responsiveness. CONCLUSION: SSBP associated with LSD1 risk allele status is driven by women with a depleted 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 (MR) activation and/or LSD1 epigenetic regulation of the MR.
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Parksook et al. (2022) conducted a cohort in Salt sensitivity of blood pressure (n=297). LSD1 risk allele (rs587618) vs. Nonrisk homozygotes was evaluated on Salt sensitivity of blood pressure and aldosterone response to angiotensin II stimulation. The LSD1 risk allele (rs587618) was associated with greater salt sensitivity of blood pressure in individuals of African descent, driven primarily by women in a low-estrogen state.
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