Genome-wide discovery of loci influencing chemotherapy cytotoxicity

The development of kidney disease is influenced by both genetic and environmental factors. Searching for models of glomerulopathy that display strong gene-environment interaction, we examined the determinants of anthracycline-induced nephropathy, a classic, strain-dependent experimental model applied to rodents in the past four decades. We produced three crosses derived from mice with contrasting susceptibility to doxorubicin (DOX) nephropathy and, surprisingly, we found that this widely studied model segregates as a single-gene defect with recessive inheritance. By genome-wide analysis of linkage, we mapped the trait locus to chromosome 16A1-B1 (DOXNPH locus) in all three crosses [peak logarithm of odds (lod) score of 92.7, P ‫؍‬ 1 ؋ 10 ؊65 ]; this interval represents a susceptibility locus for nephropathy. Gene expression analysis indicated that susceptibility alleles at the DOXNPH locus are associated with blunted expression of protein arginine methyltransferase 7 (Prmt7) on chromosome 8, a protein previously implicated in cellular sensitivity to chemotherapeutic agents (lod ‫؍‬ 12.4, P ‫؍‬ 0.0001). Therefore, Prmt7 expression serves as a molecular marker for susceptibility to DOX nephropathy. Finally, increased variation in the severity of kidney disease among affected mice motivated a second genome-wide search, identifying a locus on chromosome 9 that influences the severity and progression of nephropathy (DOXmod, peak lod score 4.3, P ‫؍‬ 0.0018). These data provide genetic and molecular characterization of a previously unrecognized Mendelian trait. Elucidation of DOX nephropathy may simultaneously provide insight into the pathogenesis of renal failure and mechanisms of cytotoxicity induced by chemotherapeutic agents.genetics

Section: Discussionmentioning

confidence: 99%

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

Zheng

Schmidt‐Ott

Chua

et al. 2005

“…Discussion EBV-transformed lymphoblasts have been used recently to demonstrate heritable variation in human gene expression (20), and specific germ-line determinants that regulate gene expression have been identified (21). Loci influencing response to chemotherapeutic drugs have also been identified by using human lymphoblastoid cell lines (22). Here, LCLs are used to demonstrate that considerable heterogeneity in the response to radiation-induced DNA damage exists within the population.…”

Section: Ebv-transformed B Lymphocytes (Lcls) From Normal Healthymentioning

confidence: 99%

Detection of functional single-nucleotide polymorphisms that affect apoptosis

Harris

Gil

Robins

et al. 2005

Human EBV-transformed B lymphocyte cell lines (LCLs) were used to measure the apoptotic response of individuals to ␥ radiation. The responses form a normal distribution around a median of 35.5% apoptosis with a range of 12-58%. This heterogeneous response has a genetic basis. LCLs from Caucasian donors and African American donors form distinct distributions of apoptotic response; all of the 11 LCLs comprising the lowest responding group (exhibiting between 12-20% apoptosis) are from Caucasian donors. The assay is capable of detecting significant effects of SNPs in two genes, MDM2 and AKT1, whose products are involved in controlling the p53 pathway and cellular response to DNA damage, suggesting that these data and this assay can be used to identify novel SNPs in other genes whose products impact the cellular response to radiation. Finally, the LCLs in the lowest apoptotic response group have the highest concentration of AKT1 protein and all harbor a haplotype in AKT1 that is present in Caucasians but absent in African Americans.

“…Recent efforts have been aimed at using genome-wide approaches in pharmacogenomic discovery both in patients (4)(5)(6) and in cell-based models (7)(8)(9)(10)(11). The majority of genome-wide significant markers identified in patients through genome-wide association studies (GWASs) were for those rare but serious adverse events, such as the flucloxacillin-induced liver injury and statin-induced myopathy (5).…”

mentioning

confidence: 99%

Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

Gamazon¹,

Huang

Cox

et al. 2010

106

109

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 ≥ 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.genome-wide association study | pharmacogenomics