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

Abstract

CYP2A6 metabolizes clinically relevant drugs, including antiretroviral and antimalarial drugs of major public health importance for the African populations. CYP2A6 genotype-phenotype relationship in African populations, and implications of geographic differences on enzyme activity, remain to be investigated. We evaluated the influence of CYP2A6 genotype, geographical differences, gender, and cigarette smoking on enzyme activity, using caffeine as a probe in 100 healthy unrelated Ethiopians living in Ethiopia, and 72 living in Sweden. CYP2A6 phenotype was estimated by urinary 1,7-dimethyluric acid (17U)/1,7-dimethylxanthine or paraxanthine (17X) ratio. The frequencies of CYP2A6*1B, *1D, *2, *4, *9, and *1x2 in Ethiopians were 31.3, 29.4, 0.6, 0.6, 2.8, and 0.3%, respectively. The overall mean -SD for log 17U/17X was 0.12 -0.24 and coefficient of variation 199%. No significant difference in the mean log 17U/17X ratio between Ethiopians living in Sweden versus Ethiopia was observed. 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. Because Omics biomarker research is rapidly accelerating in Africa, CYP2A6 pharmacogenetics and clinical pharmacology observations reported herein for the Ethiopian populations have clinical and biological importance to plan for future rational therapeutics efforts in the African continent as well as therapeutics as a global science.

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

“…Ethiopians display a distinct pharmacogenetic profile and CYP enzyme activities compared with other populations, including Caucasian, Asians, and other Black African populations. Higher CYP3A (Gebeyehu et al, 2011), CYP2A6 (Aklillu et al, 2014), CYP2B6 (Ngaimisi et al, 2013), SLCO1B1 (Aklillu et al, 2016), and CYP2D6 (Aklillu et al, 1996) enzyme activities and unique distribution of the respective variant alleles in Ethiopians compared to other populations were reported previously.…”

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

“…In contrast, Koreans display higher CYP3A (Diczfalusy et al, 2008) and NAT2 enzyme activity than Swedes (Djordjevic et al, 2012). By comparing the same population living in different geographical locations, it was reported that CYP2D6 (Aklillu et al, 2002) and xanthine oxidase (Aklillu et al, 2003) activities are significantly influenced by environmental factors, but no such effect was found for CYP2C19 or CYP2A6 (Aklillu et al, 2014).…”

Translational Genomics in Low- and Middle-Income Countries: Opportunities and Challenges

“…This picture is beginning to change with the growing pool of pharmacogenomics research [15-17] and supportive programs such as the Pharmacogenomics for Every Nation Initiative (PGENI) that aims to integrate pharmacogenetics with the public health system of LMIC by constructing a resource for relevant polymorphisms using DNA samples from major ethnic groups that represent at least 10% of the population in LMIC (www.pgeni.org/). …”