A Single Nucleotide Polymorphism in the Carboxylesterase Gene Is Associated with the Responsiveness to Imidapril Medication and the Promoter Activity

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Abstract
Imidapril is an angiotensin-converting enzyme inhibitor that is widely used in treating hypertension, although the responses vary among individuals. We investigated whether a single nucleotide polymorphism at position −816 of the carboxylesterase 1 (CES1) gene, which activates imidapril in the liver, is involved in the responsiveness to imidapril medication. A total of 105 Japanese hypertensives with systolic/diastolic blood pressures (SBP/DBP) of 140/90 mmHg or higher were prescribed 5–10 mg/day of imidapril. At baseline, blood pressure levels were not different between patients with and those without the −816C allele (AA vs. AC+CC groups). After 8 weeks of treatment, we classified the responders and non-responders based on the decline in their blood pressures, and found that the responder rate was significantly higher in the AC+CC group than in the AA group (p=0.0331). Also, the reduction in SBP was significantly greater in the AC+CC group than in the AA group (24.7±11.8 vs. 17.6±16.8 mmHg, p=0.0184). Furthermore, an in vitro reporter assay revealed that the −816C construct had significantly higher promoter activity (p<0.0001). These findings suggest that the A(−816)C polymorphism affects the transcriptional activity, and that this may account for the responsiveness to imidapril.

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