Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci.
Pharmacogenomics has employed candidate gene studies and, more recently, genome-wide association studies (GWAS) in efforts to identify loci associated with drug response and/or toxicity. The advantage of GWAS is the simultaneous, unbiased testing of millions of SNPs; the challenge is that functional information is absent for the vast majority of loci that are implicated. In the present study, we systematically evaluated SNPs associated with chemotherapeutic agent-induced cytotoxicity for six different anticancer agents and evaluated whether these SNPs were disproportionately likely to be within a functional class such as coding (consisting of missense, nonsense, or frameshift polymorphisms), noncoding (such as 3'UTRs or splice sites), or expression quantitative trait loci (eQTLs; indicating that a SNP genotype is associated with the transcript abundance level of a gene). We found that the chemotherapeutic drug susceptibility-associated SNPs are more likely to be eQTLs, and, in fact, more likely to be associated with the transcriptional expression level of multiple genes (n > or = 10) as potential master regulators, than a random set of SNPs in the genome, conditional on minor allele frequency. Furthermore, we observed that this enrichment compared with random expectation is not present for other traditionally important coding and noncoding SNP functional categories. This research therefore has significant implications as a general approach for the identification of genetic predictors of drug response and provides important insights into the likely function of SNPs identified in GWAS analysis of pharmacologic studies.
Gamazon
Eric R
ER
Sections of Genetic Medicine and Hematology/Oncology, Department of Medicine, Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA.
Huang
R Stephanie
RS
Cox
Nancy J
NJ
Dolan
M Eileen
ME
D000970:Antineoplastic Agents / Q000633:toxicity*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D020869:Gene Expression Profiling; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D020128:Inhibitory Concentration 50; D015810:Linkage Disequilibrium; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*
D000970:Antineoplastic Agents