Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Abstract

Objective: The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese. Methods and Results:The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44) (95% CI 10.7-18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; χ 2 test) among the Faroese than in other European populations (7.4%). Genotype analysis for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time PCR (TaqMan®), and we found 14.6% (n=45) (95% CI 10.8-19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population.The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e. 3.2% (95% CI 1.6-5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by PCR analysis and 2.9% (n=9) (95% CI 1.3-5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI 6.7-11.4%) and 5.3% (95% CI 3.7-7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI 5.0-9.2%). Real-time PCR (TaqMan®) was used for both CYP2C9 and CYP2C8 genotype analyses. Conclusion:The frequency of CYP2D6 poor metabolizers is two fold higher among the Faroese population compared to other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.

Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

“…Calculated allele frequencies did not differ much from those reported earlier by other studies for Caucasians, as shown in Table 2. 17,18 Incidence of GVHD No statistic differences were found in the incidence of acute GVHD grade 2-4 for EMs, IMs and PMs with 28.2, 32.8 and 25%, respectively. The genotype of donors also had no significant influence on the incidence of GVHD grade 2-4 in patients.…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…In European populations, the allele frequency of CYP2C8*3 ranges from 0.069 in Faroe Islanders to 0.198 in a Portuguese population, with an apparent north-to-south cline from lower to higher frequencies (Fig. 6;Yasar et al, 2002;Halling et al, 2005;Cavaco et al, 2006;Speed et al, 2009;1000Genomes Project Consortium, 2012Pechandova et al, 2012;Suarez-Kurtz et al, 2012). The allele is also quite common in European American and North American Hispanic populations, with frequencies of 0.09 and 0.08, respectively (Martis et al, 2013).…”

Poster presentation: Wednesday 29 August 2007

“…Introduction: The CYP2D6 polymorphism is an important determinant of TCA metabolism, and 7-10% of Europeans are CYP2D6 poor metabolizers (PM) (Alvan et al, 1990). We have recently shown an increased occurrence of CYP2D6 PMs (15%) in the Faroese population (Halling et al, 2005). Amitriptyline (AT) is the most widely used TCA.…”

“…Sparteine and metabolites were assayed by gas chromatography . CYP2D6*3, *4, *6 and *9 genotype analyses were performed by real-time polymerase chain reaction before using the Taqman technology (Halling et al, 2005) Plasma concentrations of AT and metabolites were determined by HPLC (Nielsen et al, 1993) and investigated in relation to CYP2D6 activity. Results: Of the 23 patients, five (22 % [95% CI: 7.5-43.7%]) were phenotyped and genotyped as CYP2D6 poor metabolizers (PMs).…”

“…In this population, mutations of a relevant gene, CYP2D6, occur at higher frequency than expected. A 2-fold occurrence of CYP2D6 poor metabolizers (PM) was found compared with other Caucasians (Halling et al, 2005). The CYP2D6 PM genotype and phenotype have been extensively studied as genetic risk factors for PD with inconsistent results.…”