Genetic polymorphisms in many genes related to drug Absorption, Distribution, Metabolism and Excretion (ADME genes) contribute to the high heterogeneity of drug responses in humans. Substantial genetic differences and phenotypic variation may also occur for the ADME genes across different populations. Ample evidence exists for strong inter-population differences in drug responses for specific genes, such as CYP2C9, CYP2D6 and NAT2, and for drugs such as Clopidogrel, Mercaptopurine, Omeprazole, Warfarin, etc. However, development and clinical trials of drugs in use today were predominantly carried out in populations of European ancestry from the US or Europe. Many countries, especially in the developing world, rely on US FDA/European Medicines Agency (EMEA) guidelines for safety levels and optimal therapeutic dosages. A comprehensive understanding of the inter-ethnic genetic differences in the ADME genes and their impact on drug response is therefore crucial to guide the effective global prescription of drugs.

From an evolutionary perspective, natural selection leaves a characteristic signature in specific genetic diversity patterns around the selected loci, such as high/low population differentiation levels, skewed allele frequency spectra, and/or extended haplotype homozygosity. Therefore, systematically studying signatures of natural selection on ADME genes may aid in the identification and analysis of additional functional polymorphisms.

I am therefore currently investigating the worldwide population differentiation and other signals of natural selection in a comprehensive list of ADME genes. Follow-up research based on this framework may promote the portability of many drugs across different populations.

Contact:

Dr. Jing Li

jing_lieva.mpg.de