期刊
PHARMACOTHERAPY
卷 34, 期 2, 页码 123-130出版社
WILEY
DOI: 10.1002/phar.1355
关键词
pharmacogenomics; dysglycemia; adverse metabolic effects; atenolol; Hydrochlorothiazide; hypertension; antihypertensives
资金
- National Institute of Health Pharmacogenetics Research Network [U01-GM074492]
- National Center for Advancing Translational Sciences [UL1 TR000064, UL1 TR000454, UL1 TR000135]
- Mayo Foundation
- NIH
- NIH Women's Health Initiative
- Janssen Pharmaceuticals, Inc.
- [K23 HL091120]
- [K23HL086558]
Study ObjectiveTo assess the relationship of the 33 single nucleotide polymorphisms (SNPs) previously associated with fasting glucose in Caucasians in genome-wide association studies (GWAS) with glucose response to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes. DesignRandomized, multicenter clinical trial. PatientsA total of 456 Caucasian men and women with uncomplicated hypertension. Measurements and Main ResultsThe Pharmacogenomic Evaluation of Antihypertensives Responses study evaluated blood pressure and glucose response in uncomplicated hypertensive patients randomized to either atenolol or hydrochlorothiazide (HCTZ) monotherapy, followed by combination therapy with both agents. Association of these SNPs with atenolol- or HCTZ-induced glucose response was evaluated in 456 Caucasian patients using linear regression adjusting for age, sex, body mass index, baseline glucose, baseline insulin, and principal component for ancestry. The SNP rs340874 in the 5 region of PROX1 gene was significantly associated with atenolol-induced glucose change (p=0.0013). Participants harboring the C allele of this SNP had greater glucose elevation after approximately 9weeks of atenolol monotherapy (=+2.39mg/dl per C allele), consistent with the direction of effect in fasting glucose GWAS, that showed the C allele is associated with higher fasting glucose. ConclusionThese data suggest that PROX1 SNP rs340874, discovered in fasting glucose GWAS, may also be a pharmacogenetic risk factor for antihypertensive-induced hyperglycemia. -blockers and thiazides may interact with genetic risk factors to increase risk for dysglycemia and diabetes.
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