Genome-wide association study identifies risk loci within the major histocompatibility complex region for Hunner-type interstitial cystitis

Yoshiyuki Akiyama; Kyuto Sonehara; Daichi Maeda; Hiroto Katoh; Tatsuhiko Naito; Kenichi Yamamoto; Biobank Japan Project; Takayuki Morisaki; Shumpei Ishikawa; Tetsuo Ushiku; Haruki Kume; Yukio Homma; Yukinori Okada

doi:10.1016/j.xcrm.2023.101114

Genome-wide association study identifies risk loci within the major histocompatibility complex region for Hunner-type interstitial cystitis

Cell Rep Med. 2023 Jul 18;4(7):101114. doi: 10.1016/j.xcrm.2023.101114.

Authors

Collaborators

Affiliations

¹ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³ Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
⁴ Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
⁷ Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; BioBank Japan, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁸ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁹ Department of Interstitial Cystitis Medicine, Faculty of Medicine, Kyorin University, Tokyo, Japan.
¹⁰ Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan; The Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan. Electronic address: yokada@sg.med.osaka-u.ac.jp.

Abstract

Hunner-type interstitial cystitis (HIC) is a rare, chronic inflammatory disease of the urinary bladder with unknown etiology and genetic background. Here, we conduct a genome-wide association study of 144 patients with HIC and 41,516 controls of Japanese ancestry. The genetic variant, rs1794275, in the major histocompatibility complex (MHC) region (chromosome 6p21.3) is associated with HIC risk (odds ratio [OR] = 2.32; p = 3.4 × 10^-9). The association is confirmed in a replication set of 26 cases and 1,026 controls (p = 0.014). Fine mapping demonstrates the contribution to the disease risk of a completely linked haplotype of three human leukocyte antigen HLA-DQβ1 amino acid positions, 71, 74, and 75 (OR = 1.94; p = 5 × 10^-8) and of HLA-DPβ1 amino acid position 178, which tags HLA-DPB1∗04:02 (OR = 2.35; p = 7.5 × 10^-8). The three HLA-DQβ1 amino acid positions are located together at the peptide binding groove, suggesting their functional importance in antigen presentation. Our study reveals genetic contributions to HIC risk that may be associated with class II MHC molecule antigen presentation.

Keywords: HLA; HLA imputation; Hunner; Japanese; bladder pain syndrome; genetics; genome-wide association study; interstitial cystitis; major histocompatibility complex; susceptibility.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids
Chromosomes
Cystitis, Interstitial* / genetics
Genome-Wide Association Study
Humans
Major Histocompatibility Complex / genetics

Substances

Amino Acids