The Fas Signaling Pathway Is a Common Genetic Risk Factor for Severe Cutaneous Drug Adverse Reactions Across Diverse Drugs

Abstract

Purpose: Human leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for severe cutaneous adverse drug reactions (SCARs) caused by certain drugs. However, cumulated observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. We aimed to identify a common genetic risk factor of SCARs across multiple drugs.

Methods: We performed 2 independent genome-wide association studies (GWASs). A total of 68 and 38 subjects with a diagnosis of SCAR were enrolled in each GWAS. Their allele frequencies were compared to those of healthy subjects in Korea.

Results: No single nucleotide polymorphism (SNP) with genome-wide significance was found in either GWAS. We next selected and annotated the 200 top-ranked SNPs from each GWAS. These 2 sets of annotated genes were then entered into the web interface of ConsensusPathDB for a pathway-level analysis. The Fas signaling pathway was significantly over represented in each gene set from the 2 GWASs.

Conclusions: Our observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across multiple drugs.