Lysine-Specific-Demethylase-1 Polymorphism: Interaction with Age, Salt Sensitivity of Blood Pressure and Aldosterone

Presentation Number: LB SAT 67
Date of Presentation: April 1st, 2017

Worapaka Manosroi*1 and Gordon H Williams2
1Division of Endocrinology, Diabetes, Hypertension, Boston, MA, 2Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Abstract

Background: Lysine-specific-demethylase-1 (LSD1) acts as a histone demethylase which plays an important role in epigenetic and transcription modifications. We have previous documented that 1) carriers of a cardiovascular risk allele is associated with salt sensitivity of blood pressure (SSBP) but only in African decent hypertensives; 2) LSD1 levels in several tissues vary with the level of salt intake; 3) heterozygote LSD1 knock out mice also have SSBP. Many studies have documented that aging also is associated with increased BP. Hypothesis: the interaction between age and SSBP would be modified by variants of LSD1. If present, we also assessed whether one or more components renin-angiotensin-aldosterone system (RAAS) may play a role in this interaction. Methods:A candidate gene association study was performed in 992 hypertensives (HT) and normotensives (NT) in both Caucasians and Africans from the HyperPATH cohort [HTN (n=640): NT (n=352)] with age between 18-65 years old. Rs587168 was selected as the candidate SNP. The analysis was conducted by linear regression with interaction analyses accounted for age, gender, BMI, race and disease state.

 Results: During aging the subjects with minor allele homozygotes of LSD1 (TT) were significantly more susceptible to SSBP, particularly in HTN (β=+1.55 mmHg per year*number of minor allele; P=0.02) than those with no minor allele (AA). Subjects in the TT group were found to have significantly lower aldosterone level on liberal salt intake as they age (β=-0.14 ng/dL per year*number of minor allele; P=0.04). Moreover, in the heterozygote group (AT) during aging, there was a significant association with renal plasma flow (RPF) on restricted salt intake after angiotensin II stimulation. In HTN group there was a decrease in RPF while in NT there was an increase in RPF (β=-2.7 and +3.49 cc/min/1.73m2per year*number of minor allele; P=0.02 and 0.04, respectively). No significant interaction between age and LSD1 polymorphism on renin or angiotensin II levels was observed. Conclusion Our findings support the hypothesis that LSD1 polymorphism is a crucial factor that interacts with age-associated SSBP, conferring a 15 mmHg/10 year increased risk of SSBP. In part, the mechanism may be secondary to decreased RPF, especially in HT, resulting in increased salt retention and SSBP. These findings support a potentially important role for LSD1 minor allele carrier status in population risk assessment in older and HT. Carrier status may be a marker to initiate early strategies to prevent the development of SSBP.

 

Nothing to Disclose: WM, GHW