TY - JOUR
T1 - Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study
AU - Irvin, Marguerite R.
AU - Lynch, Amy I.
AU - Kabagambe, Edmond K.
AU - Tiwari, Hemant K.
AU - Barzilay, Joshua I.
AU - Eckfeldt, John H.
AU - Boerwinkle, Eric
AU - Davis, Barry R.
AU - Ford, Charles E.
AU - Arnett, Donna K.
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
KW - SCNN1A
KW - amlodipine
KW - angiotensin-converting enzyme
KW - chlorthalidone
KW - hypertension treatment
KW - lisinopril
KW - reninangiotensinaldosterone system
KW - thiazide diuretics
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U2 - 10.1097/HJH.0b013e32833c7a4d
DO - 10.1097/HJH.0b013e32833c7a4d
M3 - Article
C2 - 20577119
AN - SCOPUS:77957281447
SN - 0263-6352
VL - 28
SP - 2076
EP - 2083
JO - Journal of Hypertension
JF - Journal of Hypertension
IS - 10
ER -