Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population: phenotypic-genotypic correlates.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Balram
C
C
Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore.
Sharma
A
A
Sivathasan
C
C
Lee
Edmund J D
EJ
D001208:Asia / Q000208:ethnology; D016572:Cyclosporine / Q000493:pharmacokinetics*; D005091:Exons; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D005828:Genetics, Population; D005838:Genotype; D016027:Heart Transplantation; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length
D007166:Immunosuppressive Agents; D016572:Cyclosporine