Journal
AMERICAN JOURNAL OF HYPERTENSION
Volume 25, Issue 7, Pages 812-817Publisher
OXFORD UNIV PRESS
DOI: 10.1038/ajh.2012.43
Keywords
blood pressure; epigenetic; genetics; hypertension; LSD-1; salt-sensitivity
Categories
Funding
- The National Institutes of Health (NIH) [HL47651, HL59424, DK63214, HL094452, HL67974]
- Specialized Center of Research (SCOR) in Molecular Genetics of Hypertension [P50HL055000]
- HTN-IR cohort [P50-HL55005]
- Cedars-Sinai Medical Center [M01-RR000425]
- University of Southern California [M01-RR000043]
- National Center for Biomedical Computing (NCBC) [LM008748, P30DK063491]
- Harvard Catalysts [UL1 RR025758]
- NIH [T32 HL007609, K23 HL084236, KL2 RR025757]
- Harvard Catalyst/NIH [5 KL2 RR025757]
- AHA Scientist Development Grant [0735609T]
- Cedars-Sinai Board of Governors'Chair in Medical Genetics
- [i2b2]
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BACKGROUND Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP). METHODS Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1(+/-)) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American). RESULTS LSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1(+/-) mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1(+/-) mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1(+/-) mice, decreased alpha-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers. CONCLUSION The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.
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