The immune factors have complex causal regulation effects on inflammatory bowel disease

Abstract

Background: Although a correlation between immune cell phenotypes and inflammatory bowel disease (IBD) has been established, a causal relationship remains unestablished.

Methods: To assess causal associations between immune cell phenotypes and IBD and its subtypes, we employed Mendelian randomization (MR) methods and genome-wide association studies (GWAS) summary statistics. The primary outcomes were determined based on the inverse variance weighting (IVW) results, with the assessment of heterogeneity and pleiotropy conducted through Cochrane's Q-test and MR-Egger. The stability of the MR results was then examined using leave-one-out analysis, and false discovery rate (FDR) correction was applied to evaluate the strength of the causal relationship between exposure and outcome. Furthermore, to identify immunophenotypes strongly associated with IBD, a meta-integration of the effect values of all positive results in both datasets was conducted.

Results: The analysis of 731 immune cell phenotypes and IBD using MR techniques revealed potential causal associations between 26 phenotypes and IBD. Subsequent meta-integration of the two datasets provided evidence of solid causal associations between 18 immune phenotypes and IBD and its subtypes. Nominal causal associations were also identified in the remaining eight immune phenotypes and IBD and its subtypes.

Conclusion: Our study confirms causal solid associations between 18 immune phenotypes and IBD, thus guiding future clinical studies.

Keywords: Crohn’s disease; Mendelian randomization; causal relationship; inflammatory bowel disease; ulcerative colitis.

Figure 1

(A) The diagram of MR assumption; (B) Diagram of MR analysis processing. SNPs, single nucleotide polymorphisms; GWAS, genome-wide association study; MR, Mendelian randomization; IBD, Inflammatory Bowel Disease; CD, Crohn’s disease; UC, ulcerative colitis; IVs instrumental variables; IVW, inverse variance weighting; MR-Egger, MR-Egger regression; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.

Figure 2

Forest plot of meta-analysis of causal estimation of immune phenotypes for IBD. NSNP, Number of SNPs; OR, odds ratio; CI, confidence interval of OR; IVW, inverse variance weighting; IBD, Inflammatory Bowel Disease; IBDGC, The International Inflammatory Bowel Disease Genetics Consortium; IEU, MRC Integrative Epidemiology Unit; HLA, human leukocyte antigen; FDR, false discovery rate.

Figure 3

Forest plot of meta-analysis of causal estimation of immune phenotypes for CD. NSNP, Number of SNPs; OR, odds ratio; CI, confidence interval of OR; IVW, inverse variance weighting; CD, Crohn’s disease; IBDGC, The International Inflammatory Bowel Disease Genetics Consortium; IEU, MRC Integrative Epidemiology Unit; HLA, human leukocyte antigen; FDR, false discovery rate.

Figure 4

Forest plot of meta-analysis of causal estimation of immune phenotypes for UC. NSNP, Number of SNPs; OR, odds ratio; CI, confidence interval of OR; IVW, inverse variance weighting; UC, ulcerative colitis; IBDGC, The International Inflammatory Bowel Disease Genetics Consortium; IEU, MRC Integrative Epidemiology Unit; HLA, human leukocyte antigen; FDR, false discovery rate.