title: Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study.
abstract: BACKGROUND
  Several clinical studies report increased risk of diabetes mellitus with pharmacologic treatment for hypertension (HTN). HTN genes may modify glycemic response to antihypertensive treatment.
  
  
  METHODS
  The current study examined the association of 24 single nucleotide polymorphisms (SNPs) in 11 HTN candidate genes with fasting glucose measured at 2, 4, and 6 years after treatment initiation. The study sample included participants free of diabetes at baseline in the Genetics of Hypertension Associated Treatment (GenHAT) study (N = 9309). GenHAT participants were randomized to receive treatment with a diuretic (chlorthalidone), calcium channel blocker (amlodipine), or angiotensin-converting enzyme (ACE) inhibitor (lisinopril). Mixed models for repeated measures were employed to test for gene and pharmacogenetic associations with fasting glucose during follow-up.
  
  
  RESULTS
  Fasting glucose at year 2 increased on average 6.8, 4.8 and 3.0 mg/dl from baseline in the chlorthalidone, amlodipine and lisinopril groups, respectively. Carrying the I allele (rs1799752) of the ACE I/D polymorphism was associated with lower fasting glucose levels (P = 0.02). Additionally, an ACE promoter polymorphism (-262, rs4291) was associated with lower fasting glucose for the model AA/AT vs. TT, which remained significant after correction for multiple testing (P = 0.001). Finally, a SNP in the α-subunit of the amiloride-sensitive epithelial sodium channel (SCNN1A, rs2228576) modified the association of amlodipine vs. chlorthalidone treatment with fasting glucose (P < 0.001).
  
  
  CONCLUSIONS
  Further examination of these genes and their relationships with cardiometabolic disease could foster development of pharmacogenetic guidelines aimed to prevent increases in fasting glucose during antihypertensive treatment.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.forename: Amy I
authors.initials: AI
authors.lastname: Lynch
authors.forename: Edmond K
authors.initials: EK
authors.lastname: Kabagambe
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Barzilay
authors.forename: John H
authors.initials: JH
authors.lastname: Eckfeldt
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
authors.forename: Charles E
authors.initials: CE
authors.lastname: Ford
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000368:Aged; D017311:Amlodipine / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002752:Chlorthalidone / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000453:epidemiology; D004232:Diuretics / Q000627:therapeutic use; D004311:Double-Blind Method; D053503:Epithelial Sodium Channels / Q000235:genetics; D005215:Fasting / Q000097:blood*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D017706:Lisinopril / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D004232:Diuretics; D053503:Epithelial Sodium Channels; C507045:SCNN1A protein, human; D017311:Amlodipine; D017706:Lisinopril; D002752:Chlorthalidone