| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 96 === Human cytochrome P450 (CYP) 3A is a major P450 enzyme found in the liver and gastrointestinal tract. It plays an important role in the metabolism of a wide variety of drugs, some endogenous steroids and harmful environmental contaminants. It has been shown that CYP3A allele encoding enzymes with little or no activity are largely created by single nucleotide polymorphisms (SNPs) in the sequences of these genes. The most prevalent of these SNPs are often of low allelic frequency, and many are specific to certain ethnic groups. Therefore, an accurate determination of their frequency in any given ethnic population requires investigations involving large sample sizes. A genotyping chip with enzyme-colorimetric detection was developed and used for simultaneous analysis of 22 known CYP3A SNPs in 451 Han Chinese subjects. Following multiplex polymerase chain reaction and allele-specific primer extension labeling, an enzymatic colorimetry detection system was employed to visualize genotype patterns on a nylon membrane. With this robust system, accurate discrimination ratios were obtained, and approximately 9,922 genotypes were determined. We found that the major four CYP3A SNPs in the Chinese subjects were CYP3A4*4 (allele frequency 2.4%), CYP3A4*5 (0.7%), CYP3A4*18A (2.7%) and CYP3A5*3C (70.2%). Most of the major CYP3A4 SNPs found in other ethnicities were not found in this study. Using the four SNPs, 11 haplotypes were identified. Comparison between present and previous studies shows that CYP3A4*4 and CYP3A4*5 alleles were Chinese-specific. The genotyping chip developed in this study is an efficient, economic and accurate system for screening multiple SNPs in a large population. Application of such technology is expected to be less labor intensive and easier to adapt to specific searches when compared with other methodologies. In addition, 169 subjects were screened for plasma steady-state concentration of nifedipine (Adalat® OROS), an in vivo marker of CYP3A activity. Most of CYP3A alleles found here on nifedipine plasma steady-state concentration had no statistical correlation when the overall cohort was analysed; however, in a separate analysis according to gender, it was revealed that the significant effect of CYP3A5 alleles were attributable to males only (p = 0.036). Nifedipine plasma steady-state concentration was significantly higher in men compared with women (1315.1 ± 941.5 versus 868.6 ± 746.5 ng/mL/g; p = 0.012) in the CYP3A5 defective subjects.
The study sought to explore if androgen receptor gene (AR) polymorphisms are associated with the risk of urothelial carcinoma (UC) which is male-predominant. AR CAG and GGN repeat lengths were analyzed in 277 UC cases and 280 age and sex-matched controls by direct sequencing of leukocyte DNA. Smoking habits were obtained using a structured questionnaire interview. Relative risks were compared between groups categorized by all possible cutoffs of AR CAG and GGN repeat lengths. Men and women who had 23 and 44 (cumulative) CAG repeats had a significantly greater risk of UC, respectively (OR 2.09, 95% CI 1.05 to 4.17, p = 0.036 and OR 4.95, 95% CI 1.56 to 15.73, p = 0.007). Amongst males who were medium-dose cigarette smokers, those who had 23 CAG and shorter GGN (< 22) repeats, had an elevated risk than those with longer CAG and GGN (OR 4.32 and 4.57, p = 0.034 and 0.042, respectively). However, neither CAG nor GGN affected the UC risk in non-smokers or heavy smokers (³ 25 packs per day-years). AR CAG polymorphism may affect the risk of UC in both genders. In addition, AR polymorphisms may influence carcinogenic effect of medium-dose of cigarette smoking in men.
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