Association of Genetic Variants of HLA-DQA1 with Bullous Pemphigoid Induced by Dipeptidyl Peptidase-4 Inhibitors.

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Several factors, including an antidiabetic (dipeptidyl peptidase-4 inhibitor; DPP-4i), have been reported to trigger BP. To identify genetic variants associated with BP, genome-wide association study (GWAS) and human leukocyte antigen (HLA) fine-mapping analysis were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (DPP-4i-BP) and 737 controls (1st cohort) and the 8 cases and 164 controls (2nd cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significance association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of noninflammatory DPP-4i-BP (allele T carrier of 72.4 % [21/29] in cases vs. 15.3% [138/901] in controls; dominant model, odds ratio [OR] = 14, P = 1.8 ×10). HLA fine-mapping revealed that HLA-DQA1*05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the combined cohort of noninflammatory DPP-4i-BP (79.3% [23/29] cases vs. 16.1% [145/901] controls; dominant model, OR = 21, P = 2.0 × 10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on noninflammatory DPP-4i-BP.