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Differential effect of ABCB1 haplotypes on promoter activity.

ABSTRACT: OBJECTIVE:Promoter single-nucleotide polymorphisms (SNPs) of the ABCB1 gene, encoding the placental efflux transporter P-glycoprotein, can affect its expression and alter xenobiotic transfer from the maternal to the fetal circulation. Because SNPs are arranged in specific combinations as defined haplotypes, the aims of this study were to: (i) determine the placental haplotype structure of the ABCB1 promoter and (ii) determine the differential effect of these haplotypes on placental ABCB1 promoter activity. MATERIALS AND METHODS:DNA samples from 100 healthy placentas were PCR-amplified and sequenced to identify existing SNPs in the proximal ABCB1 promoter. The haplotype structure encompassing these SNPs was inferred by PHASE analysis. Luciferase reporter constructs representing these haplotypes were generated and transfected into human placental 3A cells and their effect on ABCB1 promoter activity was determined using a dual-luciferase assay. RESULTS:We identified 12 ABCB1 promoter SNPs. These SNPs were predicted by PHASE to segregate into 28 haplotypes with frequencies ranging between 0.019 and 0.88. We found 12 of these haplotypes in our population in addition to two haplotypes not predicted by PHASE. We also generated two haplotypes to determine individual SNP effects for a total of 16 studied. Compared with the ancestral haplotype, three haplotypes significantly up-regulated (107-266% increase; P<0.05), one significantly down-regulated (95.4% decrease; P<0.01), and 12 had no statistically significant effect on ABCB1 promoter activity. DISCUSSION AND CONCLUSION:Our data show that the effect of SNPs on promoter activity depends on their presence in a specific haplotype. This indicates that haplotypes, rather than individual SNPs, could play a significant role in regulating placental P-glycoprotein expression and affect placental transfer and fetal exposure to xenobiotics.

SUBMITTER: Speidel JT

PROVIDER: S-EPMC5792297 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Differential effect of ABCB1 haplotypes on promoter activity.

Speidel Jordan T JT Xu Meixiang M Abdel-Rahman Sherif Z SZ

Pharmacogenetics and genomics 20180301 3

<h4>Objective</h4>Promoter single-nucleotide polymorphisms (SNPs) of the ABCB1 gene, encoding the placental efflux transporter P-glycoprotein, can affect its expression and alter xenobiotic transfer from the maternal to the fetal circulation. Because SNPs are arranged in specific combinations as defined haplotypes, the aims of this study were to: (i) determine the placental haplotype structure of the ABCB1 promoter and (ii) determine the differential effect of these haplotypes on placental ABCB1 ...[more]

PMID: 29232306

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Project description:INTRODUCTION:The human multidrug resistance gene ATP-binding cassette B1 (ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anticancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene that may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C-->T, 2677G-->T and 3435C-->T, have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related. METHODS:In this study, 95 individuals representative of the entire ethnic make-up of the USA were compared with 101 individuals from an Ashkenazi-Jewish population. These individuals were analyzed by genomic sequencing and polymerase chain reaction, using restriction fragment length polymorphisms, to calculate their genotype frequencies. RESULTS:A total of 25 SNPs were located in the exons of the ABCB1 gene. All of the polymorphisms identified were in parts of the ABCB1 gene product predicted to be intracellular, and 16 appear to be novel as compared with those listed by the National Center for Biotechnological Information. Frequencies of the 1236C-->T and 2677G-->T/A/C SNPs were similar for the US and Ashkenazi populations (64.2 and 60.4%, respectively for 1236C-->T [chi2: 0.30; p < or = 1]; 55.8 and 64.4%, respectively for 2677G-->T/A/C [chi2: 1.49; p < or = 1]), but were different for 3435C-->T (24.2% for the US population and 69.3% for the Ashkenazi population [chi2: 39.927; p < or = 0.001]). The 1236T/ 2677T/3435T haplotype occurred in 23.6% (standard error: 0.013) of the Ashkenazi population. CONCLUSION:The SNP at location 3435C-->T plays a significant role in the ABCB1 gene. The haplotype and genotype analysis from these data may be used as a basis for studies on the relationship between ABCB1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes.

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Differential effect of ABCB1 haplotypes on promoter activity.

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Differential effect of ABCB1 haplotypes on promoter activity.

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