FREQUENCY OF C3435 MDR1 AND A6896G CYP3A5 SINGLE NUCLEOTIDE POLYMORPHISM IN AN IRANIAN POPULATION AND COMPARISON WITH OTHER ETHNIC GROUPS

It is well recognized that different patients respond in different ways to medications. The inter-individual variations are greater than the intera- individual variations, a finding consistent with the notion that inheritance is a determinant of drug responses. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in this interindividual variation. Single nucleotide polymorphism in common metabolic pathway, cytochrome P450 and common transporter, multidrug resistance-1 gene are two important sites that might involve clinically significant genetic variations. Ethnicity greatly influences these genetic polymorphism distributions. We studied the inheritance patterns of polymorphisms for MDR1 andCYP3A5 genes in the Iranian population and compared its genotype and allele frequencieswith 3 different ethnic groups: Caucasian (United Kingdom), Chinese and Japanese. We found striking differences in the distribution of MDR allelic variantsbetween Iranian, Japanese and Chinese (p<0.02) and similar between the Iranian and Caucasian population. (p=0.06). Almost 50% of Iranian and Caucasian individuals were homozygous carriers of the variant T allele compared with 32% of the Japanese and 43% of the Chinese (p<0.02). More than half of Iranian subjects have at least one T allele, with lower P-gp level in small intestine. We also noted dramatic differences in the CYP3A5 alleles and genotypes distribution between Iranian subjects with other compared populations. 99% of Iranian individuals were homozygous carriers of the variant G allele compared with about 70% of the Chinese and Japanese and 19% of the Caucasian population. The G/G genotype has a very low level of active cytochrome P450 enzyme. Our results emphasize the role of ethnicity in interindividual variability of the pharmacokinetic and pharmacodynamic characteristics of drugs.