Shared genetic susceptibility between idiopathic inflammatory myopathies and common B cell lymphoma subtypes found primarily in the human leucocyte antigen region.

Abstract

Objectives: To estimate shared genetic susceptibility between major subtypes of idiopathic inflammatory myopathies (IIM) and B cell lymphomas.

Methods: We paired summary statistics from genome-wide association studies (GWASs) of diffuse large B cell lymphoma, follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL) and marginal zone lymphoma with those of dermatomyositis (DM) and polymyositis (PM) from a GWAS and an ImmunoChip study. We estimated local genetic correlation (r_g) for each disease pair using local analysis of (co)variant association (Bonferroni-corrected p value<0.05) and identified genetic variants jointly associated with both diseases using pleiotropy-informed false discovery rate (conjunctional false discovery rate <0.05). Functional mapping and annotation analyses were also performed.

Results: We identified significant r_g (ranging from -0.50 to 0.84) across 16 loci, with half located in the human leucocyte antigen (HLA) region, for the disease pairs of IIM and B cell lymphoma subtypes. Furthermore, jointly associated single-nucleotide polymorphisms were predominantly found in the HLA region. Specifically, all disease pairs showed shared genetic susceptibility in the HLA class I regions, while additional correlations in class III and class II regions were specific to DM and PM disease pairs, respectively. For some non-HLA loci with significant r_g, functional analyses revealed immune-related responses potentially overlapping between DM and FL, DM and CLL, and PM and CLL.

Conclusion: We revealed that DM and PM share genetic susceptibility with common B cell lymphoma subtypes in both immune-related loci and loci with unclear biological functions. These novel findings improve our understanding of the pathological link between IIM and B cell lymphomas.