Genetic analysis of SNPs in and around the MDRI gene locus

Abstract

The ABCB1/MDR1 multidrug transporter is the prototype of drug transporters and one of the major determinants of drug/xenobiotics response. The MDR1 gene, together with several other important drug-response genes, namely the ABCB4/MDR3 gene and the CYP3A gene cluster, maps to a 12 Mb region around Chromosome 7q21.1. A large number of studies here reported associations between MDR1/CYP3A genetic polymorphisms and a diversity of functional traits including gene expression, pharmacokinetic properties as well as susceptibilities to various diseases. Functional polymorphisms were also identified at the CYP3A4 and CYP3A5 gene loci. As polymorphisms in genes controlling drug response may influence an individuala??s response to medication, it is necessary to understand this important drug-response locus, localizing the causative variants and clarifying how its genetic variants affect function. This thesis describes a series of studies aimed at addressing the above questions, using the MDR1 gene and several nearby drug-response genes as models. Specifically, comprehensive SNP profiling was carried out in and around these genes in 5 major world populations: Chinese, Malay, Indian, Caucasian and African American. The relationships between individual markers were described in terms of linkage disequilibrium (LD) profiles; and the haplotype frequencies were estimated using Expectation Maximization (EM) approaches and compared amongst the different populations. We detected substantial, but highly variable and complex LD at this 12Mb region of Chromosome 7q21.1. Haplotype frequencies vary amongst populations, with the African population being the most different from the non-African populations. We further investigated the impact of natural selection at these gene loci through several tests including a modified Long Range Haplotype (LRH) test and Fst / Pexcess based tests. The MDR1 and MDR3 genes demonstrated significant evidence of positive selection for several variants residing on a common extended haplotype, in the 4 non-African groups. Tests of positive selection, including the LRH approach and Fst / Pexcess tests together revealed strong signatures of selection at the CYP3A gene cluster in Caucasians. We further examined the association between SNPs / haplotypes of SNPs within the MDR1 gene with Parkinsona??s disease. Several MDR1 polymorphisms were found to significantly affect onea??s susceptibility to Parkinsona??s disease. The studies described in this thesis are amongst the first efforts to clarify the genetic profiles at this important drug-response region at Chromosome 7q21.1. We presented the genetic relationships of several functionally associated drug-response genes at this chromosome locus. Our studies would provide a basis for future studies directed at single locus in different populations to be compared systematically. It should also facilitate the inference of the genomic location of causative variants. The evidences of natural selection demonstrated in our studies are among the first to be reported for genes important for drug response. These evidences strongly support the notion that genes controlling drug/xenobotics responses were under substantial selection pressures during recent human migrations. Additionally, the approaches for detecting signatures of natural selection and functional association, applied and evaluated in our studies could contribute to the identification of other functional variants in the genome.