Brant, Steven R

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Objective Perianal Crohn’s disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B ( CFB ). Design Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. Results Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB , in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. Conclusion pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

AbstractIntroductionThere are concerns regarding the effectiveness and safety of SARS‐CoV‐2 vaccine in inflammatory Bowel Disease (IBD) patients. This systematic review and meta‐analysis comprehensively summarises the available literature regarding the safety and effectiveness of SARS‐CoV‐2 vaccine in IBD.MethodsThree independent reviewers performed a comprehensive review of all original articles describing the response of SARS‐CoV‐2 vaccines in patients with IBD. Primary outcomes were (1) pooled seroconversion rate SARS‐CoV‐2 vaccination in IBD patients (2) comparison of breakthrough COVID‐19 infection rate SARS‐CoV‐2 vaccination in IBD patients with control cohort and (3) pooled adverse event rate of SARS‐CoV‐2 vaccine. All outcomes were evaluated for one and two doses of SARS‐CoV‐2 vaccine. Meta‐regression was performed. Probability of publication bias was assessed using funnel plots and with Egger’s test.ResultsTwenty‐one studies yielded a pooled seroconversion rate of 73.7% and 96.8% in IBD patients after one and two doses of SARS‐CoV‐2 vaccine respectively. Sub‐group analysis revealed non‐statistically significant differences between different immunosuppressive regimens for seroconversion. Meta‐regression revealed that the vaccine type and study location independently influenced seroconversion rates. There was no statistically significant difference in breakthrough infection in IBD patients as compared to control after vaccination.ConclusionIn summary, the systematic review and meta‐analysis suggest that SARS‐CoV‐2 vaccine is safe and effective in IBD patients.

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn’s disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.