Analytics of HLA-DQ Association in Lichen Planus

Aim: HLA-DQ associated diseases are difficult to analyze because of possible trans heterodimer effects. Lichen planus (LP), an inflammatory disease affecting squamous epithelia, was recently shown to be primarily associated with DQB1*05:01. This association is stronger in non-oral (non-OLP, mostly cutaneous, OR=1.99) versus oral (OLP OR=1.34) LP, two clinical variants of the disease. Pursuing on this, we performed a high- HLA fine-mapping to clarify the HLA association and its relationship to LP subtypes.

Methods: Deep electronic health registry data in FinnGen DF12 and records of clinic of diagnosis were used. OLP(n=3,651) and non-OLP (n=4,808) subgroupings. 490,211 individuals without an LP ICD diagnosis were used as controls. HLA imputation was carried out in FinnGen using HIBAG. HLA haplotypes are denoted by alleles separated by “~”. HLA heterodimers are denoted by alleles separated by “/”.

Results: Highest risk was conferred by presence of DQA1*01:05~DQB1*05:01 followed by presence of DQA1*01:01~DQB1*05:01; other DQ1 alleles had no susceptibility effects by themselves. DQA1*01:01~DQB1*05:01 homozygous had twice the risk of DQA1*01:01~DQB1*05:01 heterozygous. Interestingly, DQA1*01~DQB1*05/06 in trans of DQA1*01:01~DQB1*05:01 carried increased susceptibility as DQA1*01:01~DQB1*05:01 homozygous, suggesting susceptibility effects of any DQA1*01/DQB1*05:01 heterodimer.
In subjects not carrying DQB1*05:01, DRB1*15:01~DQA1*01:02~DQB1*06:02 was protective, more so 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 HLA-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.

Conclusion: DQB1*05:01 association in LP is largely invariant to DQA1 polymorphisms across LP subtypes. Other effects differing by LP subtypes were found. The invariance to DQA1 polymorphisms in LP may facilitate the identification of potential pathological epitopes. This is distinct of other DQ1 associated diseases, such as anti-Iglon5 and narcolepsy, where DQA1 polymorphism strongly influence risk. The effect of trans-heterodimer in these diseases illustrates the need to analyze HLA-DQ-associated diseases with methods beyond simple conditioning.