Identifying Common Genetic Etiologies Between Inflammatory Bowel Disease and Related Immune-Mediated Diseases

Xianqiang Liu; Dingchang Li; Yue Zhang; Hao Liu; Peng Chen; Yingjie Zhao; Piero Ruscitti; Wen Zhao; Guanglong Dong

doi:10.3390/biomedicines12112562

Identifying Common Genetic Etiologies Between Inflammatory Bowel Disease and Related Immune-Mediated Diseases

Biomedicines. 2024 Nov 8;12(11):2562. doi: 10.3390/biomedicines12112562.

Authors

Xianqiang Liu^{1

2}, Dingchang Li^{1

2}, Yue Zhang¹, Hao Liu^{2

3}, Peng Chen^{1

2}, Yingjie Zhao^{1

2}, Piero Ruscitti⁴, Wen Zhao^{2

3}, Guanglong Dong²

Affiliations

¹ Medical School of Chinese PLA, Beijing 100853, China.
² Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China.
³ School of Medicine, Nankai University, Tianjin 300071, China.
⁴ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

Abstract

Background: Patients with inflammatory bowel disease (IBD) have an increased risk of developing immune-mediated diseases. However, the genetic basis of IBD is complex, and an integrated approach should be used to elucidate the complex genetic relationship between IBD and immune-mediated diseases.

Methods: The genetic relationship between IBD and 16 immune-mediated diseases was examined using linkage disequilibrium score regression. GWAS data were synthesized from two IBD databases using the METAL, and multi-trait analysis of genome-wide association studies was performed to enhance statistical robustness and identify novel genetic associations. Independent risk loci were meticulously examined using conditional and joint genome-wide multi-trait analysis, multi-marker analysis of genomic annotation, and functional mapping and annotation of significant genetic loci, integrating the information of quantitative trait loci and different methodologies to identify risk-related genes and proteins.

Results: The results revealed four immune-mediated diseases (AS, psoriasis, iridocyclitis, and PsA) with a significant relationship with IBD. The multi-trait analysis revealed 909 gene loci of statistical significance. Of these loci, 28 genetic variants were closely related to IBD, and 7 single-nucleotide polymorphisms represented novel independent risk loci. In addition, 14 genes and 514 proteins were found to be associated with susceptibility to immune-mediated diseases. Notably, IL1RL1 emerged as a key player, present within pleiotropic genes across multiple protein databases, highlighting its potential as a therapeutic target.

Conclusions: This study suggests that the common polygenic determinants between IBD and immune-mediated diseases are widely distributed across the genome. The findings not only support a shared genetic relationship between IBD and immune-mediated diseases but also provide novel therapeutic targets for these diseases.

Keywords: GWAS; IL-1; MTAG; autoinflammation; genetics; immune-mediated diseases; inflammatory bowel disease.

Grants and funding

This research received no external funding.