Interethnic comparisons of important pharmacology genes using SNP databases: potential application to drug regulatory...

The frequencies of alleles implicated in drug-response variability provide vital information for public health management. Differences in frequencies between genetically diverse groups of individuals can hamper drug assessments, particularly in populations where clinical data are not readily available.

Making use of large, publicly available population genotype databases and population genetics tools, we developed a quick and efficient methodology to assess population divergence, which could be integrated into drug assessment and regulatory processes. To showcase its effectiveness, we present an analysis of population differences in a set of 42 important pharmacogenomics genes (PharmGKB) by utilizing allele frequencies of SNPs shared among three ethnic groups in the recently completed Singapore Genome Variation Project (Chinese, Malay and Indian) and four populations in the International HapMap project.

The analyses facilitate comparisons across populations, such as identification of genes that exhibit moderate-to-high divergence between the main ethnic groups in Singapore and Caucasians, the dominant population in most drug-development programs.

A potential use of the analyses is for regulators to develop a decision tree based on the extent of population divergence in key drug targets, metabolizing enzymes or transporter pathways when reviewing foreign clinical trial data. The methodology can be readily extended to other genes and countries with diverse ethnic groups. We continue to explore ways of integrating the information from these population genetics tools into stratifying the risk that the drug response established in one population could be translated to another.