Comparisons of CYP2A6 Genotype and Enzyme Activity between Swedes and Koreans

Abstract

The aim was to compare cytochrome P450 2A6 (CYP2A6) genotype and enzyme activity between Swedes and Koreans, and to investigate the influence of genotype, sex, age, cigarette smoking and oral contraceptive (OC) use on enzyme activity. The study involved 190 Swedes and 144 Koreans. Genotyping for CYP2A6*1B, *1×2, *4, *5, *7, *8, *9, *10, *18 and *19 alleles was done. Using caffeine as a probe, in vivo CYP2A6 activity was estimated by the 17U/17X urinary ratio. Multiple regression analysis indicated ethnicity (p=0.0001) and CYP2A6 genotype (p=0.006), but not sex, age, cigarette smoking or OC use as predictors of CYP2A6 activity. There were significant differences in CYP2A6 genotype distribution and enzyme activity between Swedes and Koreans. Functional CYP2A6 alleles and rapid genotypes were more frequent in Swedes, whereas the defective alleles and slow genotypes were more frequent in Koreans (p≤0.0001). Distribution of log 17U/17X was bimodal in Koreans but unimodal in Swedes with a common antimode at 0.01, classifying 3.16% of Swedes and 18.75% of Koreans as slow metabolizers. CYP2A6 activity was higher in Swedes compared to Koreans (p<0.0001), even among carriers of rapid genotypes. We report major differences in CYP2A6 enzyme activity between Swedes and Koreans mainly due to CYP2A6 genetic variation but not exclusively.

High CYP2A6 Enzyme Activity as Measured by a Caffeine Test and Unique Distribution of CYP2A6 Variant Alleles in Ethiopian Population

“…Analysis of variance revealed CYP2A6 genotype ( p = 0.04, F = 2.01) but not geographical differences, sex, or cigarette smoking as predictors of CYP2A6 activity. Importantly, the median (interquartile range) of 17U/17X ratio in Ethiopians 1.35 (0.99 to 1.84) was 3-and 11-fold higher than the previously reported value in Swedes 0.52 (0.27 to 1.00) and Koreans 0.13 (0.0 to 0.35), respectively (Djordjevic et al, 2013). Taken together, we report here the relevance of CYP2A6 genotype for enzyme activity in this Ethiopian sample, as well as high CYP2A6 activity and unique distribution of the CYP2A6 variant alleles in Ethiopians as compared other populations described hitherto.…”

“…We were unable to compare CYP2A6 enzyme activity in Ethiopians with other black populations due to the lack of published caffeine-based studies of CYP2A6 activity in blacks. Nevertheless, comparison using the same phenotyping strategy revealed significantly higher CYP2A6 activity in Ethiopians than Swedes or Koreans (Djordjevic et al, 2013). We observed remarkably higher CYP2A6 enzyme activity in Ethiopians than Swedes or Koreans, as measured by a caffeine phenotyping assay.…”

“…Comparing the log urinary 17U/17X data in Ethiopian with our previously published data from Swedes and Koreans (Djordjevic et al, 2013), Ethiopians display significantly higher log 17U/17X ratio and hence CYP2A6 activity as compared to Swedes (…”

“…Genotyping for gene conversion in 3¢ region (CYP2A6*1B), gene deletion (CYP2A6*4), gene duplication (CYP2A6*1x2), -1013A > G (CYP2A6*1D), -48T > G (CYP2A6*9) and 479T > A (CYP2A6*2) were performed using an allele-specific PCR method, as previously described (Djordjevic et al, 2013;Pitarque et al, 2001;Rao et al, 2000). All amplifications were performed on GeneAmp PCR System 2700 (Applied Biosystems, Foster City, CA), using the reagents purchased from Invitrogen, Carlsbad, CA, or Roche Applied Science, Mannheim, Germany.…”

“…Moreover, CYP2A6 enzyme activity appears to be affected by concomitant drug use, including rifampicin, dexamethasone, phenobarbital, and ketokonazole Tomaszewski et al, 2008) CYP2A6 enzyme activity display pronounced inter-ethnic variations between African Americans, Asians, and Caucasians (Djordjevic et al, 2010;Kandel et al, 2007;Nakajima et al, 2006), and CYP2A6 genetic variation is commonly considered as the major cause for the observed differences. Various factors such as ethnicity (Djordjevic et al, 2010(Djordjevic et al, , 2013Kandel et al, 2007;Nakajima et al, 2006), genotype Pitarque et al, 2004), sex (Kandel et al, 2007;Mwenifumbo et al, 2007), age ( Johnstone et al, 2006;Sinues et al, 2008), cigarette smoking (Djordjevic et al, 2010;Mwenifumbo et al, 2007), and oral contraceptive use (Sinues et al, 2008) are reported to influence CYP2A6 enzyme activity. However, such findings are often inconsistent (Begas et al, 2007;Djordjevic et al, 2010;Kadlubar et al, 2009;Mahavorasirikul et al, 2009), warranting further investigations.…”