Balram C, Sharma A, Sivathasan C, Lee Edmund J D
Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore.
Br J Clin Pharmacol. 2003 Jul;56(1):78-83. doi: 10.1046/j.1365-2125.2003.01820.x.
To investigate the frequency of the single nucleotide polymorphism C3435T in exon 26 of the MDR1 gene in Asians and to determine the functional significance of this SNP with the clinical pharmacokinetics of oral cyclosporin (Neoral) in 10 stable heart transplant patients.
The MDR1 C3435T polymorphism was investigated in 290 healthy Asian subjects (98 Chinese, 99 Malays and 93 Indians). We also compared the MDR1 polymorphism between the Asian population studied here and the published data on Africans and Caucasians. The clinical relevance of this SNP on oral bioavailability of a known P-gp substrate, cyclosporin, was assessed in 10 stable Chinese heart transplant patients.
The homozygous TT genotype was observed in 32%, 28% and 43% of Chinese, Malays and Indians. The homozygous CC genotype was found in 25% of Chinese and Malays compared with 18% of Indians. The Indians had a lower frequency of the C allele [0.38 (0.31-0.45)] compared with the Chinese [0.46 (0.39-0.53)] and Malays [0.48 (0.42-0.55)]. Chi-squared test showed that the distribution of allele frequencies between the Malays and Indians differed significantly (P = 0.04). In this Asian population, the overall distribution of genotypes (CC, CT and TT) and allele frequencies were significantly different from those in Africans (P < 0.001). The results were also significant when the Chinese, Malays and Indians were compared separately with the African group (P < 0.001). Compared with the Caucasian data, the overall distribution of genotype and allele frequencies in the Asian population were also significantly different (P < or = 0.05). However, when each Asian ethnic group was compared separately with the Caucasians, only the Indians were found to be significantly different (P < or = 0.004). Genotypic-phenotypic correlations of this SNP were assessed in 10 stable Chinese heart transplant patients. The median AUC(0,4 h) was 11% lower in patients with CC genotype compared with subjects with TT genotype. However, the interpatient variability in AUC(0,4 h) was high in patients, especially in those with CC genotype.
The distribution of the SNP C3435T in exon 26 in the Chinese and Malay population was found to be similar to the Caucasians whereas the Indians were different. The Asian population also differed significantly from the African and Caucasian population in the distribution of the C3435T SNP. The low frequency of the T allele in the Indian population implies lower expression of P-gp and may have important therapeutic and prognostic implications for use of P-gp dependent drugs in individuals of Indian origin.
研究亚洲人多药耐药基因1（MDR1）第26外显子单核苷酸多态性C3435T的频率，并确定该单核苷酸多态性对10例稳定期心脏移植患者口服环孢素（新山地明）临床药代动力学的功能意义。
对290名健康亚洲受试者（98名中国人、99名马来人和93名印度人）进行MDR1 C3435T多态性研究。我们还比较了本研究中的亚洲人群与已发表的非洲人和高加索人的MDR1多态性数据。在10例稳定期中国心脏移植患者中评估该单核苷酸多态性对已知P-糖蛋白底物环孢素口服生物利用度的临床相关性。
在中国人群、马来人群和印度人群中，纯合子TT基因型的比例分别为32%、28%和43%。在中国人群和马来人群中，25%的个体为纯合子CC基因型，而在印度人群中这一比例为18%。与中国人[0.46（0.39 - 0.53）]和马来人[0.48（0.42 - 0.55）]相比，印度人群中C等位基因的频率较低[0.38（0.31 - 0.45）]。卡方检验显示，马来人和印度人群之间的等位基因频率分布存在显著差异（P = 0.04）。在该亚洲人群中，基因型（CC、CT和TT）和等位基因频率的总体分布与非洲人群显著不同（P < 0.001）。当分别将中国人、马来人和印度人与非洲人群进行比较时，结果也具有显著性（P < 0.001）。与高加索人群的数据相比，亚洲人群中基因型和等位基因频率的总体分布也存在显著差异（P ≤ 0.05）。然而，当将每个亚洲种族分别与高加索人群进行比较时，仅发现印度人群存在显著差异（P ≤ 0.004）。在10例稳定期中国心脏移植患者中评估了该单核苷酸多态性的基因型 - 表型相关性。与TT基因型的受试者相比，CC基因型患者的中位药时曲线下面积（AUC）（0,4 h）低11%。然而，患者间AUC（0,4 h）的变异性较高，尤其是CC基因型的患者。
发现中国人群和马来人群中第26外显子单核苷酸多态性C3435T的分布与高加索人群相似，而印度人群则不同。亚洲人群中C3435T单核苷酸多态性的分布也与非洲人群和高加索人群存在显著差异。印度人群中T等位基因的低频率意味着P-糖蛋白表达较低，这可能对印度裔个体使用P-糖蛋白依赖性药物具有重要的治疗和预后意义。
