During the Structural Variation Consortium project, over 3000 genes have been found to be overlapped with copy number variations (CNVs), which covers as much as 12% of the human genome. Particularly, drug-associated genes are enriched within CNV regions, as well as olfactory receptors and immunoglobulin superfamilies. They include drug metabolizing genes such as CYP and UGT families, and drug transporters like ABCs. This implies that human genomes have been dynamically changing local copy number according to environmental stress including xenobiotics. Some of them are frequent in particular populations, potentially generating common response variation to drugs like chemotherapeutics, antibiotics, hormones, and alkaloids. Importantly, the HapMap SNPs are significantly under-represented in CNV regions. This is because some SNPs in these regions are not-called due to unusual signal, and others are deleted due to H-W and Mendelian inheritance errors. This indicates that any pharmacogenetic approach based on current public SNP data potentially loses these large scale polymorphisms, and more dense genotyping around CNVs and/or next generation platform will be needed for direct detection of copy numbers.
Second AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development-- Sep 17-20, 2007; Atlanta, GA