Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study

Marguerite R. Irvin, Amy I. Lynch, Edmond K. Kabagambe, Hemant K. Tiwari, Joshua I. Barzilay, John H. Eckfeldt, Eric Boerwinkle, Barry R. Davis, Charles E. Ford, Donna K. Arnett

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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. Method: 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). Conclusion: 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.

Original languageEnglish
Pages (from-to)2076-2083
Number of pages8
JournalJournal of Hypertension
Issue number10
StatePublished - Oct 2010


  • SCNN1A
  • amlodipine
  • angiotensin-converting enzyme
  • chlorthalidone
  • hypertension treatment
  • lisinopril
  • reninangiotensinaldosterone system
  • thiazide diuretics

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine


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