Ethnic differences in drug therapy: a pharmacogenomics perspective.

“Pharmacogenetics deals with pharmacological responses and their modification by hereditary influences.” This definition, offered by Werner Kalow in the first book dedicated to pharmacogenetics, highlights the three pillars of this discipline: pharmacology, genetics and human diversity [1]. Pharmacogenetics has evolved greatly over the 50 years since Kalow ́s book was published, and was rechristened pharmacogenomics (PGx) in the fashion of the ‘omics’ revolution, but its conceptual development and praxis remain contingent upon a better understanding of human genomic diversity and its impact on drug pharmacokinetics and pharmacodynamics. Ethnic specificity has become an integral part of pharmacogenetics/PGx research to the extent that, at the writing of this editorial, the PubMed database lists over 400 entries, including 141 reviews, for a query combining the terms ‘pharmacogen* and ethnicity’. The accumulated data reveal that allele, genotype and haplotype frequency of polymorphisms in ‘pharmacogenes’ (genes of pharmacological relevance) may differ significantly among populations categorized by ‘race’, ethnicity or continental origin. Such differences may be large (>50%) as is the case, for example, of the CYP3A5*3 and GSTM3*B allele frequency between Europeans and sub-Saharan Africans. However, equally large or even larger intraethnic PGx variability is also evident, such as the fivefold range of CYP3A5*3 frequency among sub-Saharan Africans or the 17-fold range of CYP2C19*2 frequency within Europeans [2,101]. Two other facts conflict with the notion of race-based drug therapy in the context of PGx-informed clinical pharmacology: first, only rarely, if ever, is a PGx polymorphism absent or common (>5%) exclusively in one specific population. Although large-scale resequencing studies of PGx candidate genes are more likely to identify low-frequency polymorphisms that are ‘private’ to a given population group, the implications of these findings on the praxis of PGx are still debatable. Second, data from a worldwide analysis of CYP2D6 polymorphisms disclosed that the patterns of variation within and among populations are best described as a broad geographic cline, with no continental structure, similar to those shown by neutral markers [3].