Fine mapping of HLA effects in Oral and non-Oral lichen planus

Lichen planus (LP) is an inflammatory disease affecting squamous epithelia, typically manifesting in a cutaneous (non-OLP) and an oral mucosa (OLP) form, the latter conferring elevated risk of oral squamous cell carcinoma. Despite presence of CD4+ and CD8+ T-cell infiltrates in LP lesions, specific autoantibodies or target T-cell antigens have not been identified. A recent genome wide association study (GWAS) uncovered 27 genome-wide independent associations, with the strongest signal within HLA class II, particularly involving DQB1*05:01 . This association showed stronger effects in non-OLP (OR=2.09) versus OLP (OR=1.36).

Here, we performed a high-resolution HLA fine-mapping analysis in FinnGen to dissect this strong class II signal and clarify its relationship to LP subtypes. We find that most DQA1*01∼DQB1*05:01 haplotypes confer increased susceptibility, with the highest risk conferred by DQA1*01:05∼DQB1*05:01 followed by DQA1*01:01∼DQB1*05:01 . In subjects not carrying DQB1*05:01 , DRB1*15:01∼DQA1*01:02∼DQB1*06:02 had a strong protective effect, more pronounced in non-OLP than OLP. Further associations were found in DRB1*09:01 and DQB1*02:02 as well as independent HLA class I associations with A*03:01 , B*08:01 and B*13:02 , all stronger in OLP versus non-OLP. Conditioning SNP associations for these effects eliminated the HLA GWAS signal.

These effects highlight that while the DQB1*05:01 association remains largely invariant to DQA1 polymorphisms across LP subtypes, the variable strength of HLA associations in non-OLP and OLP forms suggests distinct immunopathological mechanisms. The presence of trans-heterodimer effects in this disease illustrates the need to analyze HLA-DQ -associated diseases with methods beyond simple conditioning. The invariance to DQA1 polymorphisms may facilitate the identification of potential pathological epitopes.