Comparative description of haplotype structure and genetic diversity of MDR1 (ABCB1) in HIV-positive and HIV-negative populations

Abstract

Human P-glycoprotein (P-gp), encoded by MDR1 (ABCB1), is an efflux transporter with a wide specificity for substrates/drugs, including HIV protease inhibitors which are commonly used in HIV/AIDS treatment. Three single nucleotide polymorphisms (SNPs) in MDR1 have been shown to affect P-gp expression and function, and may affect HIV/AIDS treatment outcome: 1236C>T [G412G, exon-12], 2677G>T/A [A893S/T, exon-21] and 3435C>T [I1145I, exon-26]. In the present study, our aims were (i) to compare the 3-SNP MDR1 haplotype structure and genetic diversity between North American HIV-positive and HIV-negative individuals belonging to four major ethnic groups and (ii) to determine whether the haplotype structure and genetic diversity observed in these ethnically admixed populations differ from that in ethnically non-admixed populations. For these aims, we analyzed a cohort of 447 HIV/AIDS patients (White [n = 193], Black [n = 235], Hispanic [n = 17], and Asian [n = 2]). Results obtained for these patients were compared with the results for (i) HIV-negative individuals (n = 356) and (ii) various HapMap and Environmental Genome Project populations. We observed that the genetic characteristics of MDR1 were largely consistent between HIV-positive and HIV-negative populations, but there were striking interethnic differences in the genetic characteristics of MDR1 in both populations. Although it appeared that the genetic characteristics of MDR1 were largely consistent between ethnically admixed and non-admixed populations, genetic characterization of the admixed populations remains to be done. Thus, our results provide useful comparative insights about the genetic characteristics of MDR1 that could be extrapolated across population groups worldwide. For a meaningful interpretation of these results regarding HIV/AIDS treatment outcome, MDR1 haplotype/diplotype structure data, genetic characterization of population admixture, and polymorphisms in other relevant drug transporter and/or metabolizing enzyme genes should be considered in future clinical studies.

Different Frequencies of Drug Resistance Mutations among HIV-1 Subtypes Circulating in China: A Comprehensive Study

“…It was proved that host genetic polymorphism in some genes could influence the absorption, distribution, metabolism and excretion of certain drugs, and further affect drug concentration in blood, which will lead to changing of effective pressure and production of drug resistance [33] , [34] . For example, SNPs in cytochrome P450 and the ATP-binding cassette family genes can greatly affect the blood concentration of ART drugs and further put impact on treatment effectiveness [35] – [42] . Other behavioral factors, such as good adherence, were also necessary to ensure success ART treatment, which had been absolutely confirmed [43] .…”

Chemokine (C-C Motif) Receptor 5 −2459 Genotype in Patients Receiving Highly Active Antiretroviral Therapy: Race-Specific Influence on Virologic Success

“…The primers and conditions to selectively amplify CYP2B6 exons 4 and 7 [37,38], UGT2B7 exon 2 [36], and MDR1 exon 26 [39] regions have been described elsewhere. The primers and conditions to selectively amplify UGT2B7 intron 1 (411 bp), CCR2 ORF (327 bp), CCR5 promoter (1118 bp), and CCR5 ORF (312/ 280 bp) regions are described in Table 1; online only.…”

P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study

“…By selecting the appropriate hour of administration for a drug which is a (weak) substrate for P-gp, the ratio between beneficial effect and undesired side effects could be optimized. Many CNS drugs have some affinity for P-gp, e.g., certain anticancer drugs, antidepressants, and HIV-protease inhibitors (8)(9)(10)(11).…”