Allelic distributions of CYP2D6 gene copy number variation in the Eastern Han Chinese population

Abstract

Aim: The human cytochrome P450 2D6 (CYP2D6) gene copy number variation, involving CYP2D6 gene deletion (CYP2D6*5) and duplication or multiduplication (CYP2D6*×N), can result in reduced or increased metabolism of many clinically used drugs. The identification of CYP2D6*5 and CYP2D6*×N and the investigation of their allelic distributions in ethnic populations can be important in determining the right drug and dosage for each patient. Methods: The CYP2D6*5 and CYP2D6 genes, and CYP2D6 gene duplication were identified by 2 modified long PCR, respectively. To determine duplicated alleles, a novel long PCR was developed to amplify the entire duplicated CYP2D6 gene which was used as template for subsequent PCR amplification. A total of 363 unrelated Eastern Han Chinese individuals were analyzed for CYP2D6 gene copy number variation. Results: The frequency of CYP2D6*5 and CYP2D6*×N were 4.82% (n=35) and 0.69% (n=5) in the Eastern Han Chinese population, respectively. Of the 5 duplicated alleles, 3 were CYP2D6*1×N and 2 were CYP2D6*10×N. One individual was a carrier of both CYP2D6*5 and CYP2D6*1×N. Taken together, the CYP2D6 gene rearrangements were present in 10.74% of subjects. Conclusion: Allelic distributions of the CYP2D6 gene copy number variation differ among Chinese from different regions, indicating ethnic variety in Chinese. Long PCR are convenient, cost effective, specific and semiquantitative for the detection of the CYP2D6 gene copy number variation, and amplification of the entire duplicated CYP2D6 gene is necessary for the accurate identification of duplicated alleles.

CYP2D6 polymorphisms and their influence on risperidone treatment

“…Beoris et al42 found that 12.6% (n = 3,974/31,563) of all patients who were tested had zero (0.14%, 43), one (7.25%, 2,288), three or more copies of the CYP2D6 gene (≥3 copy, 5.21%, 1,643) in the American population. Sheng et al43 reported that low allele frequencies of CYP2D6*5 and CYP2D6* × N were 4.82% (n=35/363) and 0.69% (n=5/363) in the Eastern Han Chinese population, respectively, and they focused on the details of duplication and multiplication including CYP2D6*10 × N (2, 0.28%) and CYP2D6*1 × N (3, 0.41%) and also found gene rearrangement in ~11% of all the subjects. The investigations of CNV in drug biotransformation and functional enzyme activity are unclear.…”

CNVs of human genes and their implication in pharmacogenetics

“…Ultrarapid metabolizers are therefore at higher risk for therapeutic failures and might be at the risk for cardiovascular side effects when receiving a higher dosage (Brockmoller et al, 2007). (Dahl et al, 1992;Masimirembwa et al, 1993;Aklillu et al, 1996;McLellan et al, 1997;Sachse et al, 1997;Bathum et al, 1998;Yamada et al, 1998;Bernal et al, 1999;Griese et al, 1999;Wennerholm et al, 1999;Nishida et al, 2000;Ingelman-Sundberg and RodriguezAntona, 2005;Lopez et al, 2005;Lee et al, 2006;Menoyo et al, 2006;Sheng et al, 2007;Sistonen et al, 2007;Buzkova et al, 2008;Gaedigk and Coetsee, 2008). Frequency of CYP2D6 deletion in North America is given for both Caucasians and African Americans, the latter in brackets.…”

Adverse events in analgesic treatment with tramadol associated with CYP2D6 extensive-metaboliser and OPRM1 high-expression variants

“…CYP2D6 was genotyped for 35 polymorphisms using the MassARRAY system (Sequenom, San Diego, California, USA), and for gene duplication and deletion using PCRs as previously described 8. Of 160 participants genotyped, 154 (96.3%) were assigned CYP2D6 alleles according to the nomenclature and an ‘activity score’ from 0 (no activity) to 2 based on predicted allele activities 9.…”