Germline variants associated with immunotherapy-related adverse events

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses in patients across multiple cancer types, but often lead to immune related adverse events (irAEs). Although a germline cause for irAEs has been hypothesized, no systematic genome wide association study (GWAS) has been performed and no individual variants associated with the overall likelihood of developing irAEs have yet been identified. We carried out a Genome-Wide Association Study (GWAS) of 1,751 patients on ICIs across 12 cancer types, with replication in an independent cohort of 196 patients and independent clinical trial data from 2275 patients. We investigated two irAE phenotypes: (i) high-grade (3-5) events defined through manual curation and (ii) all detectable events (including high-grade) defined through electronic health record (EHR) diagnosis followed by manual confirmation. We identified three genome-wide significant associations (p<5×10⁻⁸) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined p=1.6×10⁻¹¹; hazard ratio (HR)=2.1), rs75824728 near IL22RA1 (combined p=6.6×10⁻⁹; HR=1.9), and rs113861051 on 4p15 (combined p=1.3×10⁻⁸, HR=2.0); with rs16906115 replicating in two independent studies. The association near IL7 colocalized with the gain of a novel cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation than non-carriers, and this stability was predictive of downstream irAEs and improved survival.