Search

CYP2D6*31 (4042G>A, R440H) is an allelic variant of the highly polymorphic cytochrome P450 2D6 enzyme that has been associated with reduced functional activity. The US Food and Drug Administration (FDA)-cleared AmpliChip CYP450 test detects the 4042G>A single nucleotide polymorphism (SNP) but an allele assignment could not be made in two Spanish and two Puerto Rican individuals heterozygous for 4042G>A, resulting in no-calls. We aimed to resolve the CYP2D6*31 no-calls, determine the allele haplotype, and corroborate that CYP2D6*31 is associated with a poor metabolizer phenotype. CYP2D6 genotyping was carried out using the AmpliChip CYP450 test and long-range polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) platforms. Allele haplotype was determined by cloning and sequence analysis. Allele frequencies were determined in five population samples. A 6.6-kb long-range PCR product comprising the entire CYP2D6 gene and flanking regions was sequenced to determine the CYP2D6*31 haplotype. Identical sequences were obtained from both Puerto Ricans selected for sequence analysis. One Spanish individual with a CYP2D6*4/*31 genotype was phenotyped as a poor metabolizer with the CYP2D6 probe drug dextromethorphan (urinary ratio DM/DX=0.71). The frequency of CYP2D6*31 was determined in 176 Spanish (0.57%), 50 Puerto Rican (2.0%), and 150 Hispanic (0.33%) people. CYP2D6*31 was absent in 237 North American Caucasians and 154 African Americans. CYP2D6*31 was associated with poor metabolism of dextromethorphan in vivo, which is consistent with a previous report classifying this allelic variant as nonfunctional. The discovery of CYP2D6*31 in Spanish people only (or of Spanish ancestry) suggests that it may contribute to CYP2D6 variability in individuals of Spanish ancestry. [ABSTRACT FROM AUTHOR]

Polymorphisms of the cytochrome P450 2D6 (CYP2D6) gene affecting enzyme activity are involved in interindividual variability in drug efficiency/toxicity. Four phenotypic groups are found in the general population: ultra rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. The AmpliChip CYP450 test is the first genotyping array allowing simultaneous analysis of 33 CYP2D6 alleles. The main aim of this study was to evaluate the performance of this test in CYP2D6 phenotype prediction. We first verified the AmpliChip CYP450 test genotyping accuracy for five CYP2D6 alleles routinely analysed in our laboratory (alleles 3,4,5,6, × N; n=100). Results confirmed those obtained by real-time PCR. Major improvements using the array are the detection of CYP2D6 intermediate alleles and identification of the duplicated alleles. CYP2D6 phenotype was determined by assessing urinary elimination of dextromethorphan and its metabolite dextrorphan and compared to the array prediction (n=165). Although a low sensitivity of UM prediction by genotyping was observed, phenotype prediction was optimal for PM and satisfying for EM and IM.The Pharmacogenomics Journal (2009) 9, 34–41; doi:10.1038/tpj.2008.7; published online 1 July 2008 [ABSTRACT FROM AUTHOR]