High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands

Abstract

Cytochrome P450 (CYP) 2C19 is polymorphic with poor metabolizers representing 3-6% of Europeans and Africans, and 13-23% of Asians. Greater than 99% of the poor metabolizer alleles in Asian populations are defined by two single base pair mutations (CYP2C19*2 and CYP2C19*3). We have recently reported an unprecedentedly high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals and poor metabolism of proguanil on two malarious islands of Vanuatu in eastern Melanesia. To elucidate this further, a total of 5538 individuals from 24 populations on 16 different islands of Vanuatu were genotyped. Of these, 61% had a poor metabolizer genotype (*2/*2, *2/*3 or *3/*3) with substantial variation among the populations (38-79%). The overall frequencies of CYP2C19*1 (wild-type), CYP2C19*2, and CYP2C19*3 were 0.223, 0.633, and 0.144, respectively. A significant linear correlation was observed between heterozygosity and South latitude (r = 0.552, P < 0.05). The genotype frequencies of 21 of the 24 populations were consistent with Hardy-Weinberg expectations (P > 0.05). Comparisons of genetic, linguistic and geographical patterns among populations suggest that short range gene flow is largely responsible for the current distribution of CYP2C19 alleles in Vanuatu. Taken together with previous studies of nuclear genetic loci of Pacific island populations, these data predict that the poor metabolizer genotype is common throughout Polynesia and Micronesia and may be even more prevalent in western Melanesia than in Vanuatu. This suggests that the majority of Pacific Islanders metabolize a wide variety of clinically important drugs to a significantly lower degree than the average European.