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Rare Urinary Bladder Disease GWAS Points to Importance of Autoimmunity, Inflammation

NEW YORK – Researchers in Japan have tracked down common genetic variants in an immune-related part of the genome known as the major histocompatibility complex (MHC) that are genetically associated with Hunner-type interstitial cystitis (HIC), a rare urinary bladder condition marked by urinary symptoms and bladder pain.

The findings, published in Cell Reports Medicine on Tuesday, point to a potential autoimmune aspect of the condition, consistent with inflammatory features that have been described in bladder tissue from affected individuals in the past as well as higher-than-usual rates of the condition in women.

"HIC falls under the interstitial cystitis/bladder pain syndrome (IC/BPS) umbrella, which is an ill-defined broad urological chronic pelvic pain syndrome complex clinically characterized by persistent pelvic pain/discomfort associated with [lower urinary tract symptoms], and includes a wide variety of clinical phenotypes with potentially diverse etiologies," senior and corresponding author Yukinori Okada, a researcher affiliated with the University of Tokyo, Osaka University, and the RIKEN Center for Integrative Medical Sciences, and his colleagues wrote.

The researchers searched for suspicious variants with a genome-wide association study that included 144 individuals of Japanese ancestry with HIC and more than 41,500 unaffected control individuals from the same population, including 26 HIC patients with co-occurring autoimmune conditions such as Hashimoto's thyroiditis or autoimmune hepatitis.

With imputation data from 1,037 Japanese whole-genome sequences and more than 2,500 genotyped individuals from the 1,000 Genomes Project, the team focused in on common HIC-associated variants falling in a class II human leukocyte antigen (HLA) region of the MHC locus on chromosome 6.

"Our results provide important insights into the genetic background of HIC and contribute to a better understanding of the biological basis of this disease, which may advance the clinical management and research progress in HIC," the authors reported.

After shoring up the associations with validation testing on another 26 individuals with HIC and 1,026 unaffected control individuals, the investigators fine-mapped the associations using additional insights from an HLA reference panel that included 1,118 individuals of Japanese ancestry.

In the process, the researchers narrowed their associations down to a handful of amino acid positions in the HLA-DQ-beta1 and HLA-DP-beta1 antigen genes, highlighting the potential importance of immune and antigen presentation-related processes in the condition.

"These data strongly support the hypothesis that HIC is an immune-mediated inflammatory disease that may be autoimmune in nature," the authors wrote, adding that "[f]urther exploration of rare variants by whole-genome sequencing and functional analysis of the identified risk variants, accounting for environmental interaction, may shed further light on the pathogenetic landscape of this enigmatic disease."

They noted that the current findings may lead to new avenues for more accurately diagnosing HIC and distinguishing it from other conditions with overlapping symptoms, and noted that additional research is needed in other, larger patient groups down the road to delve into the possibility of using HLA class II typing as a marker for HIC.

Moreover, the authors suggested that the current findings "may pave the way toward the development of potential therapeutic strategies for HIC targeting specific immune responses, inspired by other autoimmune disease treatments."

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