title: Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension.
abstract: 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 α-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.
  
  
  CONCLUSIONS
  The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Williams
authors.forename: Bindu
authors.initials: B
authors.lastname: Chamarthi
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Luminita H
authors.initials: LH
authors.lastname: Pojoga
authors.forename: Bei
authors.initials: B
authors.lastname: Sun
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Garza
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Gail K
authors.initials: GK
authors.lastname: Adler
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Claudio
authors.initials: C
authors.lastname: Ferri
authors.forename: Rui
authors.initials: R
authors.lastname: Fang
authors.forename: Thiago
authors.initials: T
authors.lastname: Leonor
authors.forename: Jinrui
authors.initials: J
authors.lastname: Cui
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Yii-Der
authors.initials: YD
authors.lastname: Ida Chen
authors.forename: Anny
authors.initials: A
authors.lastname: Xiang
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Raffel
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchanan
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Williams
authors.forename: Yujiang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D001741:Black or African American / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D044127:Epigenesis, Genetic; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics*; D007668:Kidney / Q000201:enzymology; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010641:Phenotype; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*
chemical_list: D017673:Sodium Chloride, Dietary; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating