reirrac50*1AQDALHA-BPharmacogenomics (PGx) is a research area aimed at identifying genetic 21(%)100806040200P = 2.0 ×× 10-10, odds ratio:2179.3%BP patients(n=29)Glu45HLA-DQbb(DQB1)16.1%Control(n=901)HLA-DQaa(DQA1)Ser75Lys175Thr107, Leu156,Glu161, Lys163factors associated with drug responses, including drug efficacy, adverse drug reactions, and the appropriate drug dosage on a case-by-case basis. To promote the clinical implementation of PGx testing, currently of limited use in clinical practice, recent research has focused on providing reliable evidence for its clinical utility. Several human leukocyte antigen (HLA) alleles have report-edly been associated with cutaneous adverse drug reactions (cADRs) induced by various drugs, significantly increasing the risk of developing cADRs. Before using drugs that are prone to cause severe cADRs, preemptive HLA genetic testing and therapeutic interventions such as drug selection and dosage adjust-ment based on the test results can reduce the incidence of cADRs in the popu-lation.Bullous pemphigoid (BP) is the most common autoimmune blistering dis-order, induced by autoantibodies mainly targeting the noncollagenous 16a domain (NC16a) of type XVII collagen (COL17). Although several factors have been reported to trigger BP, the etiology remains largely unknown. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used for the treatment of type 2 dia-betes but can sometimes induce BP. DPP-4 inhibitors work by inhibiting the action of this enzyme, thereby enhancing meal-stimulated active incretin levels, increasing insulin secretion, decreasing glucagon secretion, and improving gly-cemic control. To identify genetic variants associated with BP, a genome-wide association study (GWAS) and HLA fine-mapping analysis were conducted. The HLA fine-mapping revealed that HLA-DQA1*05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the noninflam-matory BP induced by DPP-4 inhibitors (79.3% cases vs. 16.1% controls, Fig. A). The HLA-DQα1 Ser75 polymorphism was located inside the peptide-binding pocket of HLA-DQ, suggesting the impact of HLA-DQα1 Ser75 on noninflam-matory BP induced by DPP-4 inhibitors (Fig. B).Figure: Association of genetic variants of HLA-DQA1 with BP induced by DPP-4 inhibitors(A) Association of HLA-DQA1*05 in the Japanese popu-lation with the risk of noninflammatory BP induced by DPP-4 inhibitors. (B) Noninflammatory DPP-4-induced BP risk-related amino acid positions of HLA genes. HLA amino acid positions associated with BP risk in HLA-DQ molecules are indicated on the three-dimensional ribbon models. The protein structure of HLA-DQ is based on the Protein Data Bank (PDB) entry 1jk8 and was prepared using UCSF Chimera (version 1.14). Residues in the positions with BP risk are highlighted in cyan (in the functional pocket) or yellow (outside the pocket).Recent Major PublicationsFukunaga K, Tsukagoshi E, Kurata M, Mizukawa Y, Nii-hara H, Morita E, Watanabe Y, Yamaguchi Y, Watanabe H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Azukizawa H, Asada H, Hasegawa A, Hama N, Ozeki T, Mashimo Y, Sekine A, Matsunaga K, Tanaka Y, Nakamura R, Abe R, Mushiroda T, Saito Y. Differential Effects of HLA-B*15:11 and HLA-A*31:01 on Carbamazepine-Induced Cutaneous Adverse Reactions. J Invest Dermatol 144, 908-911 (2024)Ozeki T, Muramatsu K, Yoshimoto N, Ujiie I, Izumi K, Iwata H, Mushiroda T, Ujiie H. Association of Genetic Variants of HLA-DQA1 with Bullous Pemphigoid Induced by Dipeptidyl Peptidase-4 Inhibitors. J Invest Dermatol 143, 2219-2225 (2023)Phelan J, Gomez-Gonzalez PJ, Andreu N, Omae Y, Toyo-Oka L, Yanai H, Miyahara R, Nedsuwan S, de Sessions PF, Campino S, Sallah N, Parkhill J, Smittipat N, Palittapon-garnpim P, Mushiroda T, Kubo M, Tokunaga K, Mahasiri-mongkol S, Hibberd ML, Clark TG. Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease. Nat Commun 14, 549 (2023)Invited presentationsMushiroda T. “Pharmacogenetic testing: Current status and issues” The 44th Annual Scientific Meeting of the Japanese Society of Clinical Pharmacology and Thera-peutics (Kobe, Japan) December 2023Mushiroda T. “Patient-centric stratified drug therapy based on pharmacogenomic testing” Human Genetics Asia 2023 (HGA2023) (Tokyo, Japan) October 2023Mushiroda T. “Pharmacogenetic HLA testing to avoid se-vere cutaneous adverse drug reactions” The 31st Annual Meeting of the Japanese Society for Histocompatibility and Immunogenetics (Tokyo, Japan) September 2023Mushiroda T. “Clinical implementation of pharmaco-genetic biomarkers” The 53rd Annual Meeting of the Japanese Society of Neuropsychopharmacology (Tokyo, Japan) September 2023Mushiroda T. “Patient-friendly stratified drug therapy based on pharmacogenomic testing” The 44th Pharma-cological and Therapeutic Society of Thailand Meeting (Bangkok, Thailand / Online) May 2023Laboratory for PharmacogenomicsTeam Leader: Taisei Mushiroda
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