Protein quantitative trait loci identify novel candidates modulating cellular response to chemotherapy.
Annotating and interpreting the results of genome-wide association studies (GWAS) remains challenging. Assigning function to genetic variants as expression quantitative trait loci is an expanding and useful approach, but focuses exclusively on mRNA rather than protein levels. Many variants remain without annotation. To address this problem, we measured the steady state abundance of 441 human signaling and transcription factor proteins from 68 Yoruba HapMap lymphoblastoid cell lines to identify novel relationships between inter-individual protein levels, genetic variants, and sensitivity to chemotherapeutic agents. Proteins were measured using micro-western and reverse phase protein arrays from three independent cell line thaws to permit mixed effect modeling of protein biological replicates. We observed enrichment of protein quantitative trait loci (pQTLs) for cellular sensitivity to two commonly used chemotherapeutics: cisplatin and paclitaxel. We functionally validated the target protein of a genome-wide significant trans-pQTL for its relevance in paclitaxel-induced apoptosis. GWAS overlap results of drug-induced apoptosis and cytotoxicity for paclitaxel and cisplatin revealed unique SNPs associated with the pharmacologic traits (at p<0.001). Interestingly, GWAS SNPs from various regions of the genome implicated the same target protein (p<0.0001) that correlated with drug induced cytotoxicity or apoptosis (p ≤ 0.05). Two genes were functionally validated for association with drug response using siRNA: SMC1A with cisplatin response and ZNF569 with paclitaxel response. This work allows pharmacogenomic discovery to progress from the transcriptome to the proteome and offers potential for identification of new therapeutic targets. This approach, linking targeted proteomic data to variation in pharmacologic response, can be generalized to other studies evaluating genotype-phenotype relationships and provide insight into chemotherapeutic mechanisms.
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
Amy L
AL
Stark
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America; Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America.
Ronald J
RJ
Hause
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
Lidija K
LK
Gorsic
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
Nirav N
NN
Antao
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
Shan S
SS
Wong
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America.
Sophie H
SH
Chung
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America.
Daniel F
DF
Gill
Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America.
Hae K
HK
Im
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
Jamie L
JL
Myers
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America; Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
Kevin P
KP
White
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America; Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America; Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, United States of America.
Richard Baker
RB
Jones
Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America; Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America; Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois, United States of America.
M Eileen
ME
Dolan
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D010597:Pharmacogenetics / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D020543:Proteome / Q000235:genetics; D040901:Proteomics / Q000379:methods; D040641:Quantitative Trait Loci / Q000187:drug effects* / Q000235:genetics*; D014157:Transcription Factors; D059467:Transcriptome / Q000235:genetics
D000970:Antineoplastic Agents; D011506:Proteins; D020543:Proteome; D014157:Transcription Factors; D017239:Paclitaxel; D002945:Cisplatin