Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample

Abstract

Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure. In addition to cytochrome P450 2D6, which plays a critical role in drug metabolism, ABCB1 encoded P-glycoprotein (PGP) is also an important determinant in drug bioavailability. The genes encoding these molecules are highly variable among populations and, given their clinical importance in drug therapy, determining CYP2D6 and ABCB1 allele frequencies in specific populations is very important for useful application in clinical settings. In this study the frequency of the pharmacologically relevant CYP2D6*3, *4, *5, *6 allelic variants and gene duplication, and ABCB1 C1236T and C3435T gene polymorphisms and their haplotypes was determined in a population sample of 100 Portuguese healthy subjects. CYP2D6 allele frequencies were 1.4% (*3), 13.3% (*4), 2.8% (*5), 1.8% (*6) and 6.1% (gene duplication), with 5% of the individuals classified as PM and 8.4% as UM. The frequencies obtained for the non-functional alleles and for the CYP2D6 gene duplication are in agreement with other South European populations, and reinforce the previously suggested south/north gradient of CYP2D6 duplications. Allelic frequencies for the ABCB1 polymorphisms were 52% (3435C) and 54% (1236C) and the most common haplotype (1236C-3435C) occurred with a frequency of 45.5%. Although allele and haplotype frequency data for ABCB1 in Southern Europe is limited, some discrepancies were found with other European populations, with possible therapeutic implications for PGP substrate drugs.

Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population

“…From the CYP2D6 alleles 12, whereas both CYP2C19*2 and CYP2C19*3 variants were identified in the studied Hungarian population. We found that the distributions of the most common CYP2D6 variants (*1‐*6) and gene duplications correspond well with the data of other European white populations . Prevalence of predicted phenotypes PM (8.3%) and UM (1.9%) also mirror to the North‐South gradient theory.…”

“…It is interesting to note that studies in the African populations observed far more frequent prevalence (73%–90%) of the 3435C allele and 3435C/C genotype. It is assumed that over‐dominance of 3435 C/C genotype may contribute to a selective resistance to gastrointestinal tract infections . The genotypes of G2677T/A SNP are more diverse because guanine can be changed to either thymine or adenine .…”

“…In addition to CYP450 2D6 and 2C19 metabolism, the drug absorption mediated by the ABCB1 transporter protein is also a determinant in drug bioavailability . The ABCB1 protein encoded by the multidrug resistance 1 gene ( mdr1 ) is an ATP‐dependent efflux pump for a wide variety of compounds including many frequently used drugs.…”

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

“…Genotyping for CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6 gene duplication and ABCB1 rs1128503 (c.1236C4T, p.G412G) and rs1045642 (c.3435C4T, p.I1145I) polymorphisms was performed as described earlier. 25 Marker HTR2A rs6311 (c.-1438G4A) were genotyped according to the method described by Hinney et al 26 Detection of the DRD2 rs1800497 (c.2137G4A, p.E712K), HTR2C rs6318 (c.68G4C, p.C23S), rs3813928 (c.-995G4A) and rs3813929 (c.-759C4T), BDNF rs6265 (c.196G4A, p.V66M), HTR6 rs9659997 (c.715-2542C4T) and DRD3 rs6280 (c.25T4C, p.S9G) polymorphisms was genotyped by PCR-RFLP (Supplementary Table 1). Only SNPs in Hardy-Weinberg equilibrium at the 5% significance level were further analysed.…”

First report on the distribution of 3435C>T ABCB1/MDR1polymorphism in healthy Bosniak population

“…Several preclinical and clinical studies have provided evidence for Letter to the Editor naturally occurring polymorphisms of the ABCB1/MDR1 gene and their effects on drug absorption, distribution, and elimination, as well as risk of diseases (2)(3)(4). The frequencies of the T allele in Western European countries were similar: 46% in France, 48% in Spain and Portugal, 51% in Germany, 52% in Scotland, and 54% in the UK (11)(12)(13)(14)(15)(16). However, in Middle European countries the 3435T allele frequencies proved to be far more different: e.g., 45% in Croatians, 48% in Italians, and 59% in Danes (6)(7)(8).…”