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

Takeshi Ozeki; Ken Muramatsu; Norihiro Yoshimoto; Inkin Ujiie; Kentaro Izumi; Hiroaki Iwata; Taisei Mushiroda; Hideyuki Ujiie

doi:10.1016/j.jid.2023.04.017

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

J Invest Dermatol. 2023 Nov;143(11):2219-2225.e5. doi: 10.1016/j.jid.2023.04.017. Epub 2023 May 6.

Authors

Takeshi Ozeki¹, Ken Muramatsu², Norihiro Yoshimoto², Inkin Ujiie², Kentaro Izumi², Hiroaki Iwata², Taisei Mushiroda¹, Hideyuki Ujiie³

Affiliations

¹ Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
² Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
³ Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Electronic address: h-ujiie@med.hokudai.ac.jp.

PMID: 37156394
DOI: 10.1016/j.jid.2023.04.017

Abstract

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 the genetic variants associated with BP, GWAS and HLA fine-mapping analyses were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (i.e., DPP-4i-induced noninflammatory BP) and 737 controls (first cohort) and the 8 cases and 164 controls (second cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significant association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of DPP-4i-induced noninflammatory BP (allele T carrier of 72.4% [21 of 29] in cases vs. 15.3% [138 of 901] in controls; dominant model, OR = 14, P = 1.8 × 10^-9). 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 DPP-4i-induced noninflammatory BP (79.3% [23 of 29] cases vs. 16.1% [145 of 901] controls; dominant model, OR = 21, P = 2.0 × 10^-10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on DPP-4i-induced noninflammatory BP.