Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations

Abstract

The MDR1 multidrug transporter plays a key role in determining drug bioavailability, and differences in drug response exist amongst different ethnic groups. Numerous studies have identified an association between the MDR1 single nucleotide polymorphism (SNP) exon 26 3435C>T and differences in MDR1 function. We performed a haplotype analysis of the MDR1 gene in three major ethnic groups (Chinese, Malays and Indians) by examining 10 intragenic SNPs. Four were polymorphic in all three ethnic groups: one occurring in the non-coding region and three occurring in coding exons. All three coding SNPs (exon 12 1236C>T, exon 21 2677G>T/A and exon 26 3435C>T) were present in high frequency in each ethnic group, and the derived haplotype profiles exhibited distinct differences between the groups. Fewer haplotypes were observed in the Malays (n = 6) compared to the Chinese (n = 10) and Indians (n = 9). Three major haplotypes (> 10% frequency) were observed in the Malays and Chinese; of these, two were observed in the Indians. Strong linkage disequilibrium (LD) was detected between the three SNPs in all three ethnic groups. The strongest LD was present in the Chinese, followed by Indians and Malays, with the corresponding LD blocks estimated to be approximately 80 kb, 60 kb and 40 kb, respectively. These data strongly support the hypothesis that strong LD between the neutral SNP exon 26 3435C>T and a nearby unobserved causal SNP underlies the observed associations between the neutral SNP and MDR1 functional differences. Furthermore, strong LD between exon 26 3435T and different unobserved causal SNPs in different study populations may provide a plausible explanation for conflicting reports associating the same exon 26 3435T allele with different MDR1 functional changes.

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

“…The first genetic polymorphism of MDR1 to be identified was a G2677T variant isolated from human adrenal, liver, and kidney samples that results in an Ala893Ser change in Pglycoprotein (19,20 (21)(22)(23)(24)(25)(26)(27)(28). Table I gives a summary of 19 segregating sites, resulting in 20 coding region variants identified in a population of 247 healthy individuals of different ethnic backgrounds (22).…”

“…The power to detect variants was highest in Caucasians and African Americans as sample size was considerably larger in these populations compared to other ethnic groups. There is also increasing data on variant segregation in Asians, whereas data on individuals with other ethnic backgrounds are still limited (22,24,28). Of particular interest is the large discrepancy in allele frequency of the common C1236T, G2677T, and C3435T variants between Caucasians and African Americans (21,22).…”

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

“…[17][18][19] We observed significant association with ABCB1 SNPs rs1128503, rs2032582, and rs1045642, although only rs1128503 remained significant after Bonferroni correction. It should be noted, however, that SNPs, rs1128503, rs2032582, and rs1045642, are not independent but are in strong linkage disequilibrium, 14 therefore application of …”

“…Of note, we selected the three most commonly studied ABCB1 SNPs (rs1128503, rs2032582, rs1045642), which are in strong linkage disequilibrium with high minor allele frequencies (410%) in Chinese, Malays and Indians. 13,14 Genotyping Using extracted DNA, SNP genotyping was performed using multiplex minisequencing and TaqMan SNP genotyping assays. In addition, DNA sequencing was employed to validate any borderline or ambiguous genotype data obtained from the multiplex minisequencing or TaqMan assays.…”

“…Moreover, linkage studies in Chinese, Malays, and Indians have disclosed that the T-allele of SNPs rs1128503, rs2032582, and rs1045642 are in strong linkage disequilibrium. 14 Hence, the observed preferential transmission of the T-alleles of these SNPs could be due to a haplotype effect that needs to be further evaluated.…”