Dataset Information

Exploration of the potential causative genes for inflammatory bowel disease: Transcriptome-wide association analysis, Mendelian randomization analysis and Bayesian colocalisation.

ABSTRACT:

Background

Inflammatory bowel disease (IBD) poses a complex challenge due to its intricate underlying mechanisms, and curative treatments remain elusive. Consequently, there is an urgent need to identify genes causally associated with IBD.

Methods

We extracted blood eQTL data from the GTExv8.ALL.Whole_Blood database, genome-wide association studies (GWAS) summary statistics of IBD from the IEU GWAS database, and performed a three-fold analysis protocol, including transcriptome-wide association analysis, Mendelian randomisation analysis, Bayesian colocalisation, and subsequent potential therapeutic agents identification.

Results

We identified four pathogenic genes, namely CARD9, RTEL1, STMN3 and ARFRP1, that promote the development of IBD, encompassing both ulcerative colitis (UC) and Crohn's disease (CD). Notably, ARFRP1 exhibited the ability to suppress IBD (encompassing UC and CD) development. Regarding drug prediction, cyclophosphamide emerged as a promising novel therapeutic option for IBD, encompassing UC and CD.

Conclusion

We identified several potential genes related to IBD (UC and CD), including CARD9, RTEL1, STMN3 and ARFRP1, warranting further investigation in functional studies to elucidate underlying disease mechanisms. Additionally, clinical studies exploring the potential of cyclophosphamide as a treatment avenue for IBD are warranted.

SUBMITTER: Luo Q

PROVIDER: S-EPMC11015108 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

Exploration of the potential causative genes for inflammatory bowel disease: Transcriptome-wide association analysis, Mendelian randomization analysis and Bayesian colocalisation.

Luo Qinghua Q Wang Jiawen J Ge Wei W Li Zihao Z Mao Yuanting Y Wang Chen C Zhang Leichang L

Heliyon 20240406 7

<h4>Background</h4>Inflammatory bowel disease (IBD) poses a complex challenge due to its intricate underlying mechanisms, and curative treatments remain elusive. Consequently, there is an urgent need to identify genes causally associated with IBD.<h4>Methods</h4>We extracted blood eQTL data from the GTExv8.ALL.Whole_Blood database, genome-wide association studies (GWAS) summary statistics of IBD from the IEU GWAS database, and performed a three-fold analysis protocol, including transcriptome-wid ...[more]

PMID: 38617957

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Project description:BackgroundInflammatory bowel disease (IBD) and ankylosing spondylitis (AS) share common traits of chronic recurrent inflammation affecting both the intestines and joints. Epidemiological studies have revealed that the incidence of AS has jumped from 0.3% to 3% among patients with IBD. However, these findings do not definitively establish a causal relationship whereby IBD directly leads to the development of AS. Moreover, whether the activity of IBD will have an impact on this process remains a pending question.MethodsTwo-sample Mendelian randomization (MR) analyses were employed across multiple datasets to investigate the potential of IBD as a risk factor for AS. The pathogenic genes of AS were identified by MR analysis of expression quantitative trait locus. Risk scores for active and inactive patients were calculated by single-sample gene set enrichment analysis. Comparative assessments encompassing alterations in risk transcription factor activity, shifts in signaling pathways, and variances in immune cell profiles were conducted between active and inactive patients. Moreover, the correlation of immune cells and risk genes was quantified.ResultsA total of 6 MR analyses, conducted across 3 exposure datasets and 2 outcome datasets, consistently revealed that IBD substantially elevates the risk of AS development. The MR analysis of the two outcome datasets identified 66 and 54 risk genes, respectively. Notably, both the risk scores computed from the two distinct sets of risk genes were notably higher in active patients compared to their inactive counterparts. Discernible variations in the activity of risk-associated transcription factors were observed between active and inactive patients. In addition, three inflammatory pathways exhibited marked activation in active patients. Moreover, seven specific immune cell types, closely linked to disease activity, exhibited statistically significant correlations with the identified risk genes.ConclusionBy combining Mendelian randomization with transcriptome analysis, this study postulates IBD as a significant risk factor for AS, and further presents innovative evidence for the impact of IBD activity on the progression of AS.

Project description:BackgroundIdentifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD.MethodsSummary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants.FindingsGenetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stimulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The associations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis.InterpretationThe proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD.FundingSCL is supported by research grants from the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). XYW is supported by research grants from the National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041). XL is supported by research grants from the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001).

Dataset Information

Exploration of the potential causative genes for inflammatory bowel disease: Transcriptome-wide association analysis, Mendelian randomization analysis and Bayesian colocalisation.

Background

Methods

Results

Conclusion

Publications

Exploration of the potential causative genes for inflammatory bowel disease: Transcriptome-wide association analysis, Mendelian randomization analysis and Bayesian colocalisation.

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