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

Irvin MR, Lynch AI, Kabagambe EK, Tiwari HK, Barzilay JI, Eckfeldt JH, Boerwinkle E, Davis BR, Ford CE, Arnett DK
J Hypertens. 2010 28 (10): 2076-83

PMID: 20577119 · PMCID: PMC2957368 · DOI:10.1097/HJH.0b013e32833c7a4d

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.

MeSH Terms (24)

Aged Amlodipine Angiotensin-Converting Enzyme Inhibitors Antihypertensive Agents Blood Glucose Calcium Channel Blockers Chlorthalidone Diabetes Mellitus Diuretics Double-Blind Method Epithelial Sodium Channels Fasting Female Humans Hypertension Lisinopril Longitudinal Studies Male Middle Aged Pharmacogenetics Polymorphism, Single Nucleotide Retrospective Studies Risk Factors Treatment Outcome

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