Abstract Background Perianal Crohn’s disease (pCD) is a difficult-to-treat CD phenotype, yet the genetic and molecular determinants underlying pCD susceptibility and severity remain unclear. Recognised as a global research priority, we aimed to address this gap by conducting the largest genome-wide association study (GWAS) of pCD to date. Methods Participants were recruited via the IBD BioResource (IBDBR)1 and the UK IBD Genetics Consortium (UKIBDGC)2. Kinship analyses identified cross-cohort duplicates, which were retained in the IBDBR dataset. HLA alleles were imputed based on HIBAG. Only participants of genetically inferred European ancestries were included. We defined pCD+ as CD patients with perianal abscess, perianal fistula, anal stricture, or anal ulcer. Controls (pCD-) were CD patients without perianal manifestations. We identified 5,266 pCD+ and 9,675 pCD- patients in the IBDBR, and 1,172 pCD+ and 4,518 pCD- patients in the UKIBDGC. IBDBR pCD+ patients with defunctioning stoma or proctectomy (TOpClass III disease3) were classified as refractory (n = 403) and pCD+ patients without TOpClass III disease or complex fistula as non-refractory (n = 3,588). We conducted a within-case GWAS in the IBDBR cohort based on REGENIE, adjusting for genetically inferred sex, age at diagnosis, and four genetic principal components. For genome-wide significant signals, we conducted a sensitivity analysis with additional adjustment for disease location, behaviour, and follow-up time. We ran a fixed effect meta-analysis between the IBDBR and UKIBDGC cohorts for significant signals identified in the IBDBR analysis. Results The primary GWAS identified genome-wide significant signals (P 5 × 10-8) within the MHC (Figure 1A). DRB1*01:03 showed the strongest association (odds ratio OR = 1.94, 95% CI = 1.67-2.25, P = 2.79 × 10-18, Figure 1B) among HLA alleles. DRB1*01:01 retained significance after conditioning on DRB1*01:03 but became nominally significant on sensitivity analysis (P = 5.45 × 10-4), suggesting the signal was driven by confounders. We detected a previously reported signal4 in CFB (P = 1.11 × 10-8) but its significance is likely due to its linkage with DRB1*01:03 (conditional P = 9.47 × 10-4). DRB1*01:03 remained significant in sensitivity analyses and was replicated in the UKIBDGC cohort (Table 1). Carriers of DRB1*01:03 were at increased risk of refractory pCD (OR = 1.83, 95% CI: 1.21 - 2.78, P = 4.50 × 10-3). Conclusion These findings implicate DRB1*01:03 in pCD and suggest that MHC class II-mediated dysregulation of antigen presentation is a proximal driver of pathogenic T cell responses. Importantly, we report the first genome-wide significant genetic determinant of pCD, offering a potential avenue for disease stratification and therapeutic optimisation. References: 1.Parkes M. IBD BioResource: an open-access platform of 25 000 patients to accelerate research in Crohn’s and Colitis. Gut. 2019;68(9):1537-1540. doi:10.1136/gutjnl-2019-318835 2.de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017;49(2):256-261. doi:10.1038/ng.3760 3.Geldof J, Iqbal N, LeBlanc JF, et al. Classifying perianal fistulising Crohn’s disease: an expert consensus to guide decision-making in daily practice and clinical trials. Lancet Gastroenterol Hepatol. 2022;7(6):576-584. doi:10.1016/S2468-1253(22)00007-3 4.Akhlaghpour M, Haritunians T, More SK, et al. Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn’s disease and leads to impaired CFB cleavage and phagocytosis. Published online November 1, 2023. doi:10.1136/gutjnl-2023-329689 Conflict of interest: Shakweh, Eathar: Received travel grants from Lilly and Falk, support to attend meetings from AbbVie and Takeda, and speaker fees from Takeda. Zhang, Qian: No conflict of interest El Garwani, Omar: No conflict of interest Zacharias, Neha: No conflict of interest Alexander, James: James has received speaker fees from Pfizer, Abbvie, Takeda and Janssen. He has received travel grants and support to attend meetings from Lilly, Tillotts Pharma, Takeda and Celltrion. Powell, Nick: Grant: Takeda, BMS, Pfizer, Astra-Zeneca Personal Fees: Abbvie, Abivax, Allergan, Astra-Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma UK Ltd, Ferring, Galapagos, GSK, Janssen, MSD, Roche, Pfizer, Sobi, Takeda, Tillotts Anderson, Carl: Personal Fees: Carl Anderson (CAA) has received consultancy or speaker fees from Genomics plc, BridgeBio Ltd and Glaxo Smith Kline. Sebastian, Shaji: Grant: Takeda, Tillots pharma, Biogen, Pfizer, Abbvie, Johnson & Johnson, Olympus -Odin Vision Personal Fees: Tillots, Johnson & Johnson, Olympus Odin Vision, AbbVie, Takeda, Merck, Pharmacosmos, Amgen, Eli Lilly, BMS, Odin Vision Non-financial Support: Tillots, Takeda, AbbVie, Celltrion, Johnson & Johnson, Eli Lilly, Alphasigma, Ferring Pharma Hart, Ailsa: Grant: Takeda Personal Fees: Abbvie, Amgen, Arena, AZ, Falk, Celltrion, Eli Lilly, Ferring, Genentech/ Roche, GSK, Pfizer, Takeda, Napp, Pharmacosmos, Janssen (J & J), Bristol-Myers Squibb, Gilead, Galapagos, Alfasigma Parkes, Miles: Grant: Gilead, Pfizer, AstraZeneca, Galapagos, Lilly, Takeda Fachal, Laura: No conflict of interest
Shakweh et al. (Thu,) studied this question.