Fine‐Mapping of <scp>HLA</scp> Effects in Oral and Non‐Oral Lichen Planus

ABSTRACT 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 the 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 with 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 strong trans‐heterodimer effects in this disease illustrates the need to analyse HLA‐DQ ‐associated diseases with methods beyond simple conditioning. The invariance to DQA1 polymorphisms in LP may facilitate the identification of potential pathological epitopes.