Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects

Background: P-glycoprotein, the gene product of MDR1, confers multidrug res istance against antineoplastic agents but also plays an important role in t he bioavailability of common drugs in medical treatment. Various polymorphi sms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin. Objective: We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms i n a large sample of volunteers. Methods: In this study, the distribution of the major MDRI alleles was dete rmined in 461 white volunteers with the use of polymerase chain reaction an d restriction fragment length polymorphism. Results: Five amino acid exchanges were found with allelic frequencies of 1 1.2% for Asn21Asp and 5.5% for Ser400Asn, Strikingly, in exon 21 three vari ants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2 677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mu tation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the sub jects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein. Conclusion: This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for lar ge-scale clinical investigations on the functional role of MDR1 allelic var iants for bioavailability of a substantial number of drugs.