title: Functional polymorphisms in carboxylesterase1A2 (CES1A2) gene involves specific protein 1 (Sp1) binding sites.
abstract: Carboxylesterase 1 (CES1) is involved in metabolic activation of a variety of prodrugs into active derivatives and plays an important role in pharmacokinetics. We previously reported that a single nucleotide polymorphism (SNP), -816A/C of the CES1A2 gene associates with the responsiveness to an angiotensin-converting enzyme (ACE) inhibitor, imidapril, whose activity is achieved by CES1. To identify relevant functional polymorphisms, we re-sequenced the CES1A2 promoter region ( approximately 1kb) in 100 Japanese hypertensive patients. Altogether 10 SNPs and one insertion/deletion (I/D) were identified, among which seven SNPs and one I/D residing between -62 and -32 were in almost complete linkage disequilibrium (D'=1.00, r2=0.97). They consisted a minor and a major haplotype, the allele frequencies of which were 22% and 74%, respectively. The minor haplotype possessed two putative Sp1 binding sites while the major haplotype did not have any Sp1 binding site. The minor haplotype had a higher transcription and Sp1 binding activities than the major haplotype, invitro. The original -816A/C was in high linkage disequilibrium with these haplotypes (D'=0.92, r2=0.85), and well agreed with the efficacy of imidapril medication. These results suggest that the Sp1 binding site variation in the CES1A2 promoter is functional, and are good candidates for the pharmacogenetic studies of CES1-activated drugs.
authors.affiliation: Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kimura
authors.forename: Miho
authors.initials: M
authors.lastname: Ishii
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishii
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Eiichi
authors.initials: E
authors.lastname: Geshi
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muramatsu
mesh_terms: D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D043182:Carboxylesterase / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D048289:Imidazolidines / Q000493:pharmacokinetics*; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D043182:Carboxylesterase; D048289:Imidazolidines; D016329:Sp1 Transcription Factor; C065166:imidapril; C474609:CES1 protein, human; D002265:Carboxylic Ester Hydrolases