title: ABC transporters and the proteasome complex are implicated in susceptibility to Stevens-Johnson syndrome and toxic epidermal necrolysis across multiple drugs.
abstract: Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent rare but serious adverse drug reactions (ADRs). Both are characterized by distinctive blistering lesions and significant mortality rates. While there is evidence for strong drug-specific genetic predisposition related to HLA alleles, recent genome wide association studies (GWAS) on European and Asian populations have failed to identify genetic susceptibility alleles that are common across multiple drugs. We hypothesize that this is a consequence of the low to moderate effect size of individual genetic risk factors. To test this hypothesis we developed Pointer, a new algorithm that assesses the aggregate effect of multiple low risk variants on a pathway using a gene set enrichment approach. A key advantage of our method is the capability to associate SNPs with genes by exploiting physical proximity as well as by using expression quantitative trait loci (eQTLs) that capture information about both cis- and trans-acting regulatory effects. We control for known bias-inducing aspects of enrichment based analyses, such as: 1) gene length, 2) gene set size, 3) presence of biologically related genes within the same linkage disequilibrium (LD) region, and, 4) genes shared among multiple gene sets. We applied this approach to publicly available SJS/TEN genome-wide genotype data and identified the ABC transporter and Proteasome pathways as potentially implicated in the genetic susceptibility of non-drug-specific SJS/TEN. We demonstrated that the innovative SNP-to-gene mapping phase of the method was essential in detecting the significant enrichment for those pathways. Analysis of an independent gene expression dataset provides supportive functional evidence for the involvement of Proteasome pathways in SJS/TEN cutaneous lesions. These results suggest that Pointer provides a useful framework for the integrative analysis of pharmacogenetic GWAS data, by increasing the power to detect aggregate effects of multiple low risk variants. The software is available for download at https://sourceforge.net/projects/pointergsa/.
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoletti
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America; INSERM U981, Institut Gustave Roussy, Villejuif, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Guarnieri
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America; Department of Biomedical Informatics, Columbia University, New York, New York, United States of America; JP Sulzberger Columbia Genome Center, Columbia University, New York, New York, United States of America.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America; Department of Computer Science, Columbia University, New York, New York, United States of America.
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States of America; Department of Biomedical Informatics, Columbia University, New York, New York, United States of America; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, United States of America; Institute for Cancer Genetics, Columbia University, New York, NY 10032, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, United States of America; Department of Biomedical Informatics, Columbia University, New York, New York, United States of America.
authors.forename: Aris
authors.initials: A
authors.lastname: Floratos
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000465:Algorithms; D000483:Alleles; D030541:Databases, Genetic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D013262:Stevens-Johnson Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D046988:Proteasome Endopeptidase Complex