HLA-DRB3/4/5-based susceptibility profiles in nivolumab-induced type 1 diabetes and interstitial lung disease

Immune checkpoint inhibitors (ICIs) can induce severe immune-related adverse events (irAEs), including type 1 diabetes (ICI-T1D) and interstitial lung disease (ICI-ILD); however, predictive genetic markers have not yet been fully elucidated. Accordingly, this study aimed to identify genetic polymorphisms associated with susceptibility to nivolumab-induced ICI-T1D and ICI-ILD. To address this, whole-genome sequencing using next-generation sequencing was performed on genomic DNA obtained from patients recruited from multiple centers nationwide who developed ICI-T1D (n = 14), ICI-ILD (n = 58), or no irAEs (ICI-Control, n = 72) after initiation of nivolumab therapy, followed by a genome-wide association study (GWAS). The primary GWAS identified an association signal within the HLA region on chromosome 6 in the comparison between the ICI-T1D and ICI-Control groups, whereas no significant associations were detected in analyses involving the ICI-ILD group. This signal was accompanied by an increased rate of missing genotypes, most prominently around the HLA-DRB5 locus, suggesting underlying structural and haplotypic complexity within the HLA-DR region that cannot be fully resolved by reference genome-based short-read analysis alone, leading to a post hoc analysis focusing on disease-susceptibility alleles of HLA-DRB3/4/5 and their haplotypic structures in relation to HLA-DRB1, which is in strong linkage disequilibrium with these loci, with comparisons to a healthy reference population (General Controls; n = 1,320). 24 distinct HLA-DRB1 alleles and 11 distinct HLA-DRB3/4/5 alleles (including null types), and 30 distinct haplotypes were identified. Compared with General Controls, in the ICI-T1D group, HLA-DRB1*04:05:01, DRB1*08:02:01, and DRB4*01:03:01 were associated with susceptibility; in addition, the haplotypes DRB1*04:05:01-DRB4*01:03:01, DRB1*08:02:01-DRB3/4/5 null, and DRB1*09:01:02-DRB4*01:03:01 were also associated with susceptibility. For the ICI-ILD group, HLA-DRB1*08:03:02 was associated with susceptibility, and the haplotypes DRB1*04:10:03-DRB4*01:03:01 and DRB1*08:03:02-DRB3/4/5 null were also associated with susceptibility. Overall, these findings indicate that HLA class II polymorphisms, including DRB3/4/5, contribute to genetic susceptibility to ICI-related irAEs and support the extension of HLA typing beyond DRB1 to better elucidate the immunogenetic basis of these adverse events.