Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

Introduction

The cytochrome P450 superfamily are the largest family of enzymes involved in drug metabolism. The genes are highly polymorphic and contribute to the variability between individuals in drug response and adverse drug reactions. CYP2C9 is the most highly expressed isoform of the CYP2C family in the liver and is involved in the metabolism of warfarin, NSAIDs and phenytoin.

In a recent meta-analysis of CYP2C9 allele frequency from the literature, Zhou et al., examined 8 functionally relevant CYP2C9 alleles from 81,662 unrelated individuals from 70 countries and 40 ethnic groups to establish a global map of genetic variability and inferred functional consequences.

Main Points

• Analysis of the global distribution of the 2 most well studied CYP2C9 alleles (CYP2C9*2 and CYP2C9*3) showed that the decreased function allele *2 was most abundant across southern Europe and the Middle East, but low in South Asia and almost absent in East Asia and Sub-Saharan Africa (although there was a lack of data fom many southern African nations). The highly decreased/loss of function allele *3 was also frequent in European and Middle Eastern populations and rare or absent in southern Africa and East Asia, but in contrast was common in South Asia.
• Other variant alleles (*5, *6, *8, *11, *13 and *14) were examined in a total of 16 populations. The data were not as comprehensive as for the *2 and *3 alleles, but the *5 allele was most abundant in the United Arab Emirates (UAE), *6 in Sudan, with *8 and *11 most prevalent in African and South American populations.
• Prevalence of CYP2C9*2 and *3 alleles varied quite widely across the 40 ethnic groups studied, notably being quite different to the national frequency in some countries, indicating the importance of ethnic background to pharmacogenomic investigations. This could often be attributed to differences between indigenous or founder populations and migratory populations.
• Normal, intermediate and poor metaboliser phenotypes were inferred from the frequencies of the decreased function (*2, *5, *8, *11, and *14) and loss of function (*3, *6 and *13) alleles. The world-wide prevalence of poor metabolisers was low, except for the UAE (high frequency of CYP2C9*3 and *5). Intermediate metabolisers were most common in the UAE, Croatia and Iran, and generally low in Southern Africa, except for Mozambique (high frequency of CYP2C9*8).

Conclusion

Guidelines for pharmacogenetically guided dosing already exist for some commonly prescribed drugs, however the data presented in this study  highlight the need to consider the genetic variability of a population at high resolution when considering the efficacy and potential side effects of pharmacological interventions, particularly in nations or regions with a high population diversity.

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