Divergent effects of HLA-DQA1:p.Gln198Glu on trajectory in inflammatory bowel disease

Divergent effects of HLA-DQA1:p.Gln198Glu on trajectory in inflammatory bowel disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Brief Communication Divergent effects of HLA-DQA1:p.Gln198Glu on trajectory in inflammatory bowel disease Laura Fachal, Benjamin Zare, Mohmmed Sharip, Nicola Wyat, Christopher Roberts, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9569016/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Inflammatory bowel disease (IBD) is a polygenic condition, influenced by environmental factors, and demonstrating marked phenotypic heterogeneity. While genetic susceptibility is well characterised, genetic determinants of disease severity and progression remain unclear. We report the novel divergent effects of HLA-DQA1:p.Gln198Glu , associated with increased risk of complicated Crohn’s disease (odds ratio [OR]=1.15, P=2.41x10-9) and reduced severity in ulcerative colitis (OR=0.81, P=8.98x10 -12 ), particularly reduced risk for colectomy (OR=0.69, P=6.74x10 -12 ). Biological sciences/Genetics/Genetic association study/Genome-wide association studies Biological sciences/Immunology/Immunological disorders/Inflammatory diseases/Inflammatory bowel disease Figures Figure 1 Figure 2 Main Ulcerative colitis (UC) and Crohn’s disease (CD) exhibit heterogeneity in clinical presentation, disease trajectory, treatment response, and outcomes. Up to 45% of people with CD develop complications within 10 years 1 , while ~10% of people with UC will require colectomy 2 . The genetic architecture of IBD susceptibility has been extensively characterised through large-scale genome-wide association studies (GWAS), implicating over 320 IBD-associated loci 3 . However, susceptibility variants explain little of the heterogeneity in disease severity or prognosis 4,5 , and genome-wide significant associations with disease severity or complicated disease behaviour remain scarce 6 . Identifying genetic determinants of disease trajectory is an unmet need with potential clinical utility, in particular to inform treatment decisions at diagnosis. In this well-powered analysis, we identify only two genome-wide significant loci for IBD trajectory. Strikingly, one is an HLA variant with opposing effects in CD and UC representing the first genome-wide significant evidence of a single locus exerting divergent effects on disease progression across IBD subtypes. We performed a GWAS of disease trajectory in 31,679 individuals with IBD from the NIHR IBD BioResource (IBDBR) 7 and the UK-IBD Genetics Consortium (UK-IBDGC) 8 ( Supplementary Table 1 ). Meta-analysis was performed using a fixed-effect inverse-variance weighted model. Covariates included sex and four principal components (PCs). Severe UC was defined by need for colectomy or immunosuppressive treatment (immunomodulator and/or advanced therapies) (n=8,329; Fig. 1a ). Patients without these features and ≥5 years’ follow-up were classified as mild UC (n=4,392). Genome-wide significant signals were only observed in the HLA locus ( Fig. 1b ). The strongest signal was HLA-DRB1*01:03 (OR=2.41, 95%CI 1.98-2.95, P=4.54×10 -18 ; Fig. 1c ), consistent with prior studies 9,10,ref . The second strongest signal was HLA-DQA1:p.Gln198Glu (OR=0.81, 95%CI 0.77-0.86, P=8.98x10 -12 , Fig. 1c, Supplementary Table 2 ), which conferred a protective effect against severe UC. HLA-DQA1:p.Gln198Glu showed weak linkage disequilibrium (LD) with HLA-DRB1*01:03 (R 2 =0.008) and remained genome-wide significant after conditioning on this allele (OR=0.83, 95%CI 0.78-0.88, P=1.42x10 -9 ) . Meta-analysis revealed significant inter-cohort heterogeneity in effect size (P_het=3.28×10 -3 ; Supplementary Table 1 ), which we hypothesised was attributable to differences in endpoint definitions between datasets ( Online Methods ). Restricting analyses to colectomy, as a harmonised endpoint, resolved the heterogeneity (P_het=0.13; Supplementary Table 1 ), whilst maintaining the protective effect of HLA-DQA1:p.Gln198Glu (OR=0.69, 95%CI 0.62-0.76, P=6.74x10 -12 ). No additional genome-wide significant HLA allele or amino acid change associations were observed after conditioning on the effects of HLA-DRB1*01:03 and HLA-DQA1:p.Gln198Glu ( Fig. 1d, Supplementary Table 3 ). We next examined CD behaviour, ( Fig. 1e ) defining stricturing (B2) and penetrating (B3) disease as complicated CD (n=7,269). Controls were those with inflammatory (B1) disease (n=11,689). CD analyses were additionally adjusted for disease location given its correlation with CD behaviour. Genome-wide significant signals were again limited to the HLA region ( Fig. 1b ), where HLA-DQA1:p.Gln198Glu was the strongest association (OR=1.15, 95%CI 1.10-1.20, P=2.41×10 -9 , Fig. 1c, Supplementary Table 4 ). Notably, HLA-DQA1:p.Gln198Glu conferred an increased risk of complicated CD, in contrast to its effect on UC severity. No heterogeneity was observed (P_het=1.39x10 -1 ), and no significant signals remained after conditioning on HLA-DQA1:p.Gln198Glu ( Fig. 1d, Supplementary Table 5 ). A previously reported intergenic variant upstream of HLA-DQA1 (rs77005575) 6 also reached significance (P=8.58x10 -9 ). To confirm the absence of additional independent signals and identify the most likely causal variant, we performed statistical fine-mapping ( Online methods ). This identified a single association signal (posterior probability (PP) as a single causal variant=1) but was unable to resolve the causal variant due to strong LD within this region (95% PP credible set, n=148; Supplementary Table 6 ). Within this credible set, HLA-DQA1:p.Gln198Glu (PP=0.032) demonstrated a stronger association and a higher PP of causality than rs77005575 (PP=0.0097). The HLA-DQA1:p.Gln198Glu variant demonstrated divergent effects across IBD subtypes ( Fig. 2 ), similar to smoking ( Supplementary Fig. 3 ). Its effect on the degree of severity in both diseases suggests that this is unlikely due to collider bias ( Supplementary Fig. 2a ) introduced by disease subtype stratification. To further assess this, particularly its association with CD behaviour, we performed multinomial regression in a combined cohort of CD and UC patients with high diagnostic certainty ( Online methods ). With UC as the reference group, HLA-DQA1:p.Gln198Glu showed a significantly stronger effect (P=3.03x10 -6 ) on B2/3 versus B1 CD, supporting its role in complicated CD behaviour ( Supplementary Fig. 2b ). Although instances of opposing directional effects across immune-mediated traits are rarer than concordant pleiotropy 11 , precedents exist - albeit limited to susceptibility rather than severity / trajectory, as we observed here. Thus TYK2:p.Ile684Ser is protective against rheumatoid arthritis but associated with increased IBD risk, in contrast to two other TYK2-associated variants 12 ; and HLA-B*08:01 confers decreased susceptibility to CD but increased susceptibility to both UC and primary sclerosing cholangitis 13,14 . Beyond genetics, divergent effects of smoking on IBD trajectory are well established. Findings from this study have important implications for future IBD research. Our analysis demonstrates that genetic determinants of disease trajectory are uncommon in both CD and UC. Aside from HLA-DRB1*01:03 , HLA-DQA1:p.Gln198Glu was the only locus associated with trajectory at genome-wide significance in either subtype. Its presence in both diseases, but with divergent effects, is striking. Variation within these genes determines which antigens bind to HLA Class II molecules on antigen-presenting cells and are presented to T helper cells. These findings highlight CD4 T helper cell activation, and downstream effectors, as central to genetic-environmental interactions shaping IBD trajectories. The basis for the divergent effects between CD and UC remains unclear, but warrants functional investigation that may provide key insights into the mechanisms governing IBD biology. Online Methods We meta-analysed data from two large UK-based IBD cohorts: IBDBR and UK-IBDGC, comprising 31,679 IBD patients. Genotyping, quality control steps, duplicates and first degree relatives exclusions, as well as genetic PC calculations have been previously described elsewhere ref . Classical HLA alleles were imputed using HIBAG 15 , whereas amino acid variants were imputed using SNP2HLA 16 . Statistical fine-mapping was carried out with FINEMAP 17 using summary statistics and in-sample LD data, setting the following parameters: --corr-config 0.9, --n-causal-snps 1, and --pvalue-snps 1E-5. We focused on the 9,591 variants located within 500 kb of the most significant variant (chr6:32617141:A:G). A severe UC phenotype in IBDBR was defined as patients meeting ANY of the following criteria: colectomy for any indication, use of immunomodulator therapy, and/or requirement for advanced therapy (biologic or small molecule therapies approved for the treatment of moderate-severe UC). Those with a mild disease course were defined as patients meeting ALL of the following criteria with at least five years’ follow up data available: no history of colectomy (partial/total or subtotal), no use of immunomodulator therapy, and no requirement for advanced therapy. Modified definitions (based on advanced therapy use and surgery only) were used to define severity within the UK-IBDGC cohort, for which data on immunomodulator use were largely unavailable. In patients with CD, we investigated the effect of HLA-DQA1:p.Gln198Glu on surgical outcomes. Small bowel surgery included drainage of intra-abdominal abscess, ileal or jejunal resection, ileal or jejunal stricturoplasty or ileocaecal resection (right hemicolectomy) in patients with B2/B3 disease. Colonic surgery included colectomy with ileostomy, colectomy with ileoanal pouch formation, and partial colectomy in patients with colonic involvement. To minimise potential bias arising from subtype misclassification in the analysis of CD behaviour, we restricted the analysis to patients with the highest diagnostic certainty (based on clinical, endoscopic, histological and radiological diagnosis). To reduce potential collider bias related to disease stratification, we jointly analysed CD and UC to investigate the effect of HLA-DQA1:p.Gln198Glu on disease behaviour across IBD. Using UC as the reference group, we fitted a multinomial regression model to estimate the effect of DQA1:p.Gln198Glu on inflammatory CD (B1) and complicated CD (B2/B3), and tested whether the effect was greater in complicated CD than in inflammatory CD. This analysis was restricted to patients from the NIHR IBD BioResource, for whom diagnostic-certainty information was available. The analysis was adjusted for sex, four genetic PCs and disease location, with UC coded as colonic-only involvement for the location variable. Amino acid numbering in this study is based on the MANE Select transcript ENST00000343139.11; accordingly, the residue analysed here is designated p.Gln198Glu, although it has been reported as p.Gln175Glu in some other studies and HLA reference panel. Declarations Acknowledgements This research was supported by the NIHR IBD BioResource and NIHR Cambridge Biomedical Research Centre. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This research was funded by the Wellcome Trust [Grant numbers 206194 and 220540/Z/20/A], the National Institute for Health and Care Research (NIHR), the Medical Research Council, Open Targets, Crohn’s & Colitis UK, the Helmsley Charitable Trust, Crohn's in Childhood Research Association (CICRA) and our Industry partner, AstraZeneca’s Centre for Genomics Research. We thank the Wellcome Sanger Institute’s Human Genetics Informatics (HGI) and Scientific Operations teams for their support, Kavyaa Venkat for administrative support, and other members of the UKIBDGC and IBDBR. The UKIBDGC collection comprises genotyping array data, generated at the Wellcome Sanger Institute, from participants recruited through the UK IBD Genetics Consortium collection. The UKIBDGC includes recruitment centres in Cambridge (03/5/012), Edinburgh (LREC/2002/6/18, GREC/03/0273 and YREC/P12/03), Exeter (08/H0202/139, 11/SW/0222); Newcastle (22/02); London (05/Q0502/127); Oxford (11/YH/0020, 16/YH/0247); Nottingham (03/5/012); Manchester (05/Q1407/274), St Marks (09/H0717/4), and Torbay (06/Q2104/9). The NIHR IBD BioResource is a centralised national recallable platform of 50,000 patients with Crohn's disease or ulcerative colitis designed to support globally competitive scientific and clinical IBD research. IRAS number: 173561; East of England - Cambridge Central Research Ethics Committee Reference: 15/EE/0286 Data availability Genotype data from UKIBDGC that supported this study have been deposited in the European Genome-phenome Archive (EGA; https://ega-archive.org). They are available under accessions EGAD00000000005, EGAS00000000084, and EGAS00001000924, and can be accessed by application to, and following approval by, the Sanger Data Access Committee. Genotype and phenotype data from IBDBR are available via the NIHR BioResource (https://www.ibdbioresource.nihr.ac.uk/), subject to approval of a research proposal by the NIHR BioResource Data Access Committee and the completion of a signed data access agreement. References Thia, K. T., Sandborn, W. J., Harmsen, W. S., Zinsmeister, A. R. & Loftus, E. V., Jr. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology 139 , 1147–1155 (2010). Dai, N., Haidar, O., Askari, A. & Segal, J. P. Colectomy rates in ulcerative colitis: A systematic review and meta-analysis. Dig Liver Dis 55 , 13–20 (2023). Liu, Z. et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet 55 , 796–806 (2023). Lee, J. C. et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn’s disease. Nat Genet 49 , 262–268 (2017). Vestergaard, M. V. et al. Genetic Risk of Inflammatory Bowel Disease Is Associated With Disease Course Severity. Gastroenterology 170 , 721–734 (2026). Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387 , 156–167 (2016). Parkes, M. & IBD BioResource Investigators. IBD BioResource: an open-access platform of 25 000 patients to accelerate research in Crohn’s and Colitis. Gut 68 , 1537–1540 (2019). de Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet 49 , 256–261 (2017). Satsangi, J. et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 347 , 1212–1217 (1996). Vestergaard, M. V. et al. HLA-DRB1*01:03 and Severe Ulcerative Colitis. JAMA 332 , 1941–1943 (2024). Parkes, M., Cortes, A., van Heel, D. A. & Brown, M. A. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 14 , 661–673 (2013). Diogo, D. et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS One 10 , e0122271 (2015). Goyette, P. et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet 47 , 172–179 (2015). Liu, J. Z. et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 45 , 670–675 (2013). Zheng, X. et al. HIBAG--HLA genotype imputation with attribute bagging. Pharmacogenomics J 14 , 192–200 (2014). Jia, X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8 , e64683 (2013). Benner, C. et al. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics 32 , 1493–1501 (2016). Ref. Zhang, Q. et al. HLA-DRB1*01:03 in IBD: a genotype/phenotype association study. Lancet Gastroenterol Hepatol, in press Additional Declarations There is NO Competing Interest. Supplementary Files 02DQA1Supplementarynotesubmittedversion.docx Supplementary Table 1 & Supplementary Figure 1 ConsortiumAuthorship.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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UK","correspondingAuthor":false,"prefix":"","firstName":"Miles","middleName":"","lastName":"Parkes","suffix":""}],"badges":[],"createdAt":"2026-04-29 18:20:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9569016/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9569016/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108947565,"identity":"debcff1e-8c3b-461b-8798-37f07a7e70b2","added_by":"auto","created_at":"2026-05-11 06:29:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":759103,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHLA associations with UC severity and CD behaviour.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e, Severe UC definition. \u003cstrong\u003eb\u003c/strong\u003e, Manhattan plot of UC severity GWAS. \u003cstrong\u003ec, \u003c/strong\u003eAssociation statistics for HLA alleles (four-digit resolution) and amino acid variants with UC severity. \u003cstrong\u003ed,\u003c/strong\u003e Additionally conditioned on \u003cem\u003eHLA-DRB1*01:03 \u003c/em\u003eand \u003cem\u003eHLA-DQA1.pGln198Glu\u003c/em\u003e. \u003cstrong\u003ee,\u003c/strong\u003e Montreal classification for CD behaviour; B2 and B3 were defined as ‘complicated’ CD. \u003cstrong\u003ef,\u003c/strong\u003e Manhattan plot of the ‘complicated’ CD behaviour GWAS. \u003cstrong\u003eg, \u003c/strong\u003eAssociation statistics for HLA alleles (four-digit resolution) and amino acid variants with CD behaviour. \u003cstrong\u003eh,\u003c/strong\u003e Additionally conditioned on \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-9569016/v1/319f5e9046bdb075e7ec4db2.png"},{"id":108947483,"identity":"dcad7149-3b90-42cb-b55c-00ed075fabae","added_by":"auto","created_at":"2026-05-11 06:29:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":167756,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eHLA-DQA1:p.Gln198Glu\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e across the IBD disease spectrum.\u003c/strong\u003e Allele frequency of \u003cem\u003eHLA-DQA1:p.Gln198Glu \u003c/em\u003estratified by disease subtype and severity/behaviour category. Analysis restricted to individuals from the NIHR IBD BioResource.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-9569016/v1/0cbb5e5582f9414f7ada5531.png"},{"id":108947571,"identity":"15566997-de36-464e-b49a-73b4c9fa47ca","added_by":"auto","created_at":"2026-05-11 06:29:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":989514,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9569016/v1/9cd454b0-804c-4cb9-9fc6-439961928083.pdf"},{"id":108947398,"identity":"f335cd72-333e-4859-afdb-94524ab1acaf","added_by":"auto","created_at":"2026-05-11 06:28:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":249799,"visible":true,"origin":"","legend":"Supplementary Table 1 \u0026 Supplementary Figure 1","description":"","filename":"02DQA1Supplementarynotesubmittedversion.docx","url":"https://assets-eu.researchsquare.com/files/rs-9569016/v1/dd5bc9b3814ca34b91eb6b47.docx"},{"id":108947402,"identity":"06167f86-e64f-418c-b49c-5b39335db601","added_by":"auto","created_at":"2026-05-11 06:28:33","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":33004,"visible":true,"origin":"","legend":"","description":"","filename":"ConsortiumAuthorship.docx","url":"https://assets-eu.researchsquare.com/files/rs-9569016/v1/22e477274038c7f4cf9f7eae.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Divergent effects of HLA-DQA1:p.Gln198Glu on trajectory in inflammatory bowel disease","fulltext":[{"header":"Main","content":"\u003cp\u003eUlcerative colitis (UC) and Crohn\u0026rsquo;s disease (CD) exhibit heterogeneity in clinical presentation, disease trajectory, treatment response, and outcomes. Up to 45% of people with CD develop complications within 10 years\u003csup\u003e1\u003c/sup\u003e, while ~10% of people with UC will require colectomy\u003csup\u003e\u0026nbsp;2\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe genetic architecture of IBD susceptibility has been extensively characterised through large-scale genome-wide association studies (GWAS), implicating over 320 IBD-associated loci\u003csup\u003e3\u003c/sup\u003e. However, susceptibility variants explain little of the heterogeneity in disease severity or prognosis\u003csup\u003e4,5\u003c/sup\u003e, and genome-wide significant associations with disease severity or complicated disease behaviour remain scarce\u003csup\u003e6\u003c/sup\u003e. Identifying genetic determinants of disease trajectory is an unmet need with potential clinical utility, in particular to inform treatment decisions at diagnosis. In this well-powered analysis, we identify only two genome-wide significant loci for IBD trajectory. Strikingly, one is an HLA variant with opposing effects in CD and UC representing the first genome-wide significant evidence of a single locus exerting divergent effects on disease progression across IBD subtypes.\u003c/p\u003e\n\u003cp\u003eWe performed a GWAS of disease trajectory in 31,679 individuals with IBD from the NIHR IBD BioResource (IBDBR)\u003csup\u003e7\u003c/sup\u003e and the UK-IBD Genetics Consortium (UK-IBDGC)\u003csup\u003e8\u003c/sup\u003e (\u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e). Meta-analysis was performed using a fixed-effect inverse-variance weighted model. Covariates included sex and four principal components (PCs).\u003c/p\u003e\n\u003cp\u003eSevere UC was defined by need for colectomy or immunosuppressive treatment (immunomodulator and/or advanced therapies) (n=8,329; \u003cstrong\u003eFig. 1a\u003c/strong\u003e). Patients without these features and \u0026ge;5 years\u0026rsquo; follow-up were classified as mild UC (n=4,392). Genome-wide significant signals were only observed in the HLA locus (\u003cstrong\u003eFig. 1b\u003c/strong\u003e). The strongest signal was \u003cem\u003eHLA-DRB1*01:03\u003c/em\u003e (OR=2.41, 95%CI 1.98-2.95, P=4.54\u0026times;10\u003csup\u003e-18\u003c/sup\u003e; \u003cstrong\u003eFig. 1c\u003c/strong\u003e), consistent with prior studies\u003csup\u003e9,10,ref\u003c/sup\u003e. The second strongest signal was \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e (OR=0.81, 95%CI 0.77-0.86, P=8.98x10\u003csup\u003e-12\u003c/sup\u003e, \u003cstrong\u003eFig. 1c, Supplementary Table 2\u003c/strong\u003e), which conferred a protective effect against severe UC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e showed weak linkage disequilibrium (LD) with \u003cem\u003eHLA-DRB1*01:03\u0026nbsp;\u003c/em\u003e(R\u003csup\u003e2\u003c/sup\u003e=0.008) and remained genome-wide significant after conditioning on this allele (OR=0.83, 95%CI 0.78-0.88, P=1.42x10\u003csup\u003e-9\u003c/sup\u003e)\u003cem\u003e.\u003c/em\u003e Meta-analysis revealed significant inter-cohort heterogeneity in effect size (P_het=3.28\u0026times;10\u003csup\u003e-3\u003c/sup\u003e; \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e), which we hypothesised was attributable to differences in endpoint definitions between datasets (\u003cstrong\u003eOnline Methods\u003c/strong\u003e). Restricting analyses to colectomy, as a harmonised endpoint, resolved the heterogeneity (P_het=0.13; \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e), whilst maintaining the protective effect of \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e (OR=0.69, 95%CI 0.62-0.76, P=6.74x10\u003csup\u003e-12\u003c/sup\u003e). No additional genome-wide significant HLA allele or amino acid change associations were observed after conditioning on the effects of \u003cem\u003eHLA-DRB1*01:03\u0026nbsp;\u003c/em\u003eand \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e (\u003cstrong\u003eFig. 1d, Supplementary Table 3\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe next examined CD behaviour, (\u003cstrong\u003eFig. 1e\u003c/strong\u003e) defining stricturing (B2) and penetrating (B3) disease as complicated CD (n=7,269). Controls were those with inflammatory (B1) disease (n=11,689). CD analyses were additionally adjusted for disease location given its correlation with CD behaviour. Genome-wide significant signals were again limited to the HLA region (\u003cstrong\u003eFig. 1b\u003c/strong\u003e), where \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e was the strongest association (OR=1.15, 95%CI 1.10-1.20, P=2.41\u0026times;10\u003csup\u003e-9\u003c/sup\u003e, \u003cstrong\u003eFig. 1c, Supplementary Table 4\u003c/strong\u003e). Notably, \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e conferred an increased risk of complicated CD, in contrast to its effect on UC severity. No heterogeneity was observed (P_het=1.39x10\u003csup\u003e-1\u003c/sup\u003e), and no significant signals remained after conditioning on \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e (\u003cstrong\u003eFig. 1d, Supplementary Table 5\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eA previously reported intergenic variant upstream of HLA-DQA1 (rs77005575)\u003csup\u003e6\u003c/sup\u003e also reached significance (P=8.58x10\u003csup\u003e-9\u003c/sup\u003e). To confirm the absence of additional independent signals and identify the most likely causal variant, we performed statistical fine-mapping (\u003cstrong\u003eOnline methods\u003c/strong\u003e). This identified a single association signal (posterior probability (PP) as a single causal variant=1) but was unable to resolve the causal variant due to strong LD within this region (95% PP credible set, n=148; \u003cstrong\u003eSupplementary Table 6\u003c/strong\u003e). Within this credible set, \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e (PP=0.032) demonstrated a stronger association and a higher PP of causality than rs77005575 (PP=0.0097).\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e variant demonstrated divergent effects across IBD subtypes (\u003cstrong\u003eFig.\u003c/strong\u003e \u003cstrong\u003e2\u003c/strong\u003e), similar to smoking (\u003cstrong\u003eSupplementary Fig. 3\u003c/strong\u003e). Its effect on the degree of severity in both diseases suggests that this is unlikely due to collider bias (\u003cstrong\u003eSupplementary Fig. 2a\u003c/strong\u003e) introduced by disease subtype stratification. To further assess this, particularly its association with CD behaviour, we performed multinomial regression in a combined cohort of CD and UC patients with high diagnostic certainty (\u003cstrong\u003eOnline methods\u003c/strong\u003e). With UC as the reference group, \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e showed a significantly stronger effect (P=3.03x10\u003csup\u003e-6\u003c/sup\u003e) on B2/3 versus B1 CD, supporting its role in complicated CD behaviour (\u003cstrong\u003eSupplementary Fig. 2b\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough instances of opposing directional effects across immune-mediated traits are rarer than concordant pleiotropy\u003ca href=\"https://paperpile.com/c/Cfv4Gv/t5tK4\"\u003e\u003csup\u003e11\u003c/sup\u003e\u003c/a\u003e, precedents exist - albeit limited to susceptibility rather than severity / trajectory, as we observed here. Thus \u003cem\u003eTYK2:p.Ile684Ser\u0026nbsp;\u003c/em\u003eis protective against rheumatoid arthritis but associated with increased IBD risk, in contrast to two other TYK2-associated variants\u003ca href=\"https://paperpile.com/c/Cfv4Gv/DUTJ7\"\u003e\u003csup\u003e12\u003c/sup\u003e\u003c/a\u003e; and \u003cem\u003eHLA-B*08:01\u0026nbsp;\u003c/em\u003econfers decreased susceptibility to CD but increased susceptibility to both UC and primary sclerosing cholangitis\u003ca href=\"https://paperpile.com/c/Cfv4Gv/5Pida+i9BlT\"\u003e\u003csup\u003e13,14\u003c/sup\u003e\u003c/a\u003e. Beyond genetics, divergent effects of smoking on IBD trajectory are well established.\u003c/p\u003e\n\u003cp\u003eFindings from this study have important implications for future IBD research. Our analysis demonstrates that genetic determinants of disease trajectory are uncommon in both CD and UC. Aside from \u003cem\u003eHLA-DRB1*01:03\u003c/em\u003e, \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e was the only locus associated with trajectory at genome-wide significance in either subtype. Its presence in both diseases, but with divergent effects, is striking. Variation within these genes determines which antigens bind to HLA Class II molecules on antigen-presenting cells and are presented to T helper cells. These findings highlight CD4 T helper cell activation, and downstream effectors, as central to genetic-environmental interactions shaping IBD trajectories. The basis for the divergent effects between CD and UC remains unclear, but warrants functional investigation that may provide key insights into the mechanisms governing IBD biology.\u0026nbsp;\u003c/p\u003e"},{"header":"Online Methods","content":"\u003cp\u003eWe meta-analysed data from two large UK-based IBD cohorts: IBDBR and UK-IBDGC, comprising 31,679 IBD patients. Genotyping, quality control steps, duplicates and first degree relatives exclusions, as well as genetic PC calculations have been previously described elsewhere\u003csup\u003eref\u003c/sup\u003e. Classical HLA alleles were imputed using HIBAG\u003csup\u003e15\u003c/sup\u003e, whereas amino acid variants were imputed using SNP2HLA\u003csup\u003e16\u003c/sup\u003e. Statistical fine-mapping was carried out with FINEMAP\u003csup\u003e17\u003c/sup\u003e using summary statistics and in-sample LD data, setting the following parameters: --corr-config 0.9, --n-causal-snps 1, and --pvalue-snps 1E-5. We focused on the 9,591 variants located within 500 kb of the most significant variant (chr6:32617141:A:G).\u003c/p\u003e\n\u003cp\u003eA severe UC phenotype in IBDBR was defined as patients meeting ANY of the following criteria: colectomy for any indication, use of immunomodulator therapy, and/or requirement for advanced therapy (biologic or small molecule therapies approved for the treatment of moderate-severe UC). Those with a mild disease course were defined as patients meeting ALL of the following criteria with at least five years\u0026rsquo; follow up data available: no history of colectomy (partial/total or subtotal), no use of immunomodulator therapy, and no requirement for advanced therapy. Modified definitions (based on advanced therapy use and surgery only) were used to define severity within the UK-IBDGC cohort, for which data on immunomodulator use were largely unavailable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn patients with CD, we investigated the effect of \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e on surgical outcomes. Small bowel surgery included drainage of intra-abdominal abscess, ileal or jejunal resection, ileal or jejunal stricturoplasty or ileocaecal resection (right hemicolectomy) in patients with B2/B3 disease. Colonic surgery included colectomy with ileostomy, colectomy with ileoanal pouch formation, and partial colectomy in patients with colonic involvement.\u003c/p\u003e\n\u003cp\u003eTo minimise potential bias arising from subtype misclassification in the analysis of CD behaviour, we restricted the analysis to patients with the highest diagnostic certainty (based on clinical, endoscopic, histological and radiological diagnosis). To reduce potential collider bias related to disease stratification, we jointly analysed CD and UC to investigate the effect of \u003cem\u003eHLA-DQA1:p.Gln198Glu\u003c/em\u003e on disease behaviour across IBD. Using UC as the reference group, we fitted a multinomial regression model to estimate the effect of \u003cem\u003eDQA1:p.Gln198Glu\u003c/em\u003e on inflammatory CD (B1) and complicated CD (B2/B3), and tested whether the effect was greater in complicated CD than in inflammatory CD. This analysis was restricted to patients from the NIHR IBD BioResource, for whom diagnostic-certainty information was available. The analysis was adjusted for sex, four genetic PCs and disease location, with UC coded as colonic-only involvement for the location variable.\u003c/p\u003e\n\u003cp\u003eAmino acid numbering in this study is based on the MANE Select transcript ENST00000343139.11; accordingly, the residue analysed here is designated p.Gln198Glu, although it has been reported as p.Gln175Glu in some other studies and HLA reference panel.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThis research was supported by the NIHR IBD BioResource and NIHR Cambridge Biomedical Research Centre. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Wellcome Trust [Grant numbers 206194 and 220540/Z/20/A], the National Institute for Health and Care Research (NIHR), the Medical Research Council, Open Targets, Crohn\u0026rsquo;s \u0026amp; Colitis UK, the Helmsley Charitable Trust, Crohn\u0026apos;s in Childhood Research Association (CICRA) and our Industry partner, AstraZeneca\u0026rsquo;s Centre for Genomics Research. We thank the Wellcome Sanger Institute\u0026rsquo;s Human Genetics Informatics (HGI) and Scientific Operations teams for their support, Kavyaa Venkat for administrative support, and other members of the UKIBDGC and IBDBR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe UKIBDGC collection comprises genotyping array data, generated at the Wellcome Sanger Institute, from participants recruited through the UK IBD Genetics Consortium collection. The UKIBDGC includes recruitment centres in Cambridge (03/5/012), Edinburgh (LREC/2002/6/18, GREC/03/0273 and YREC/P12/03), Exeter (08/H0202/139, 11/SW/0222); Newcastle (22/02); London (05/Q0502/127); Oxford (11/YH/0020, 16/YH/0247); Nottingham (03/5/012); Manchester (05/Q1407/274), St Marks (09/H0717/4), and Torbay (06/Q2104/9).\u003c/p\u003e\n\u003cp\u003eThe NIHR IBD BioResource is a centralised national recallable platform of 50,000 patients with Crohn\u0026apos;s disease or ulcerative colitis designed to support globally competitive scientific and clinical IBD research. IRAS number: 173561; East of England - Cambridge Central Research Ethics Committee Reference: 15/EE/0286\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eData availability\u003c/h2\u003e\n\u003cp\u003eGenotype data from UKIBDGC that supported this study have been deposited in the European Genome-phenome Archive (EGA; https://ega-archive.org). They are available under accessions EGAD00000000005, EGAS00000000084, and EGAS00001000924, and can be accessed by application to, and following approval by, the Sanger Data Access Committee.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGenotype and phenotype data from IBDBR are available via the NIHR BioResource (https://www.ibdbioresource.nihr.ac.uk/), subject to approval of a research proposal by the NIHR BioResource Data Access Committee and the completion of a signed data access agreement.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eThia, K. T., Sandborn, W. J., Harmsen, W. S., Zinsmeister, A. R. \u0026amp; Loftus, E. V., Jr. Risk factors associated with progression to intestinal complications of Crohn\u0026rsquo;s disease in a population-based cohort. \u003cem\u003eGastroenterology\u003c/em\u003e \u003cstrong\u003e139\u003c/strong\u003e, 1147\u0026ndash;1155 (2010).\u003c/li\u003e\n\u003cli\u003eDai, N., Haidar, O., Askari, A. \u0026amp; Segal, J. P. 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Zhang, Q. \u003cem\u003eet al.\u003c/em\u003e HLA-DRB1*01:03 in IBD: a genotype/phenotype association study. \u003cem\u003eLancet Gastroenterol Hepatol,\u003c/em\u003e in press\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9569016/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9569016/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Inflammatory bowel disease (IBD) is a polygenic condition, influenced by environmental factors, and demonstrating marked phenotypic heterogeneity. While genetic susceptibility is well characterised, genetic determinants of disease severity and progression remain unclear.\r\nWe report the novel divergent effects of \u003ci\u003eHLA-DQA1:p.Gln198Glu\u003c/i\u003e, associated with increased risk of complicated Crohn’s disease (odds ratio [OR]=1.15, P=2.41x10-9) and reduced severity in ulcerative colitis (OR=0.81, P=8.98x10\u003csup\u003e-12\u003c/sup\u003e), particularly reduced risk for colectomy (OR=0.69, P=6.74x10\u003csup\u003e-12\u003c/sup\u003e).","manuscriptTitle":"Divergent effects of HLA-DQA1:p.Gln198Glu on trajectory in inflammatory bowel disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 06:26:15","doi":"10.21203/rs.3.rs-9569016/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0bad548-3abf-4c11-bd8b-1ccd9b0955bc","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67643436,"name":"Biological sciences/Genetics/Genetic association study/Genome-wide association studies"},{"id":67643437,"name":"Biological sciences/Immunology/Immunological disorders/Inflammatory diseases/Inflammatory bowel disease"}],"tags":[],"updatedAt":"2026-05-11T06:26:15+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 06:26:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9569016","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9569016","identity":"rs-9569016","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}