title: A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity.
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.
authors.affiliation: Third Department of Internal Medicine, Showa University School of Medicine Tokyo, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Geshi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kimura
authors.forename: Mika
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Shinji
authors.initials: S
authors.lastname: Koba
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sakai
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Saito
authors.forename: Atsuro
authors.initials: A
authors.lastname: Koga
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D043182:Carboxylesterase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D048289:Imidazolidines / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D048289:Imidazolidines; C065166:imidapril; D043182:Carboxylesterase