PMID- 36111848 OWN - NLM STAT- MEDLINE DCOM- 20230321 LR - 20230321 IS - 1876-4479 (Electronic) IS - 1873-9946 (Print) IS - 1873-9946 (Linking) VI - 17 IP - 2 DP - 2023 Mar 18 TI - An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis. PG - 277-288 LID - 10.1093/ecco-jcc/jjac121 [doi] AB - BACKGROUND AND AIMS: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. METHODS: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. RESULTS: MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 x 10-9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 x 10-19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 x 10-6]. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 x 10-8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. CONCLUSIONS: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease. CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation. FAU - Mortlock, Sally AU - Mortlock S AUID- ORCID: 0000-0003-2327-9465 AD - Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia. FAU - Lord, Anton AU - Lord A AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. AD - Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia. FAU - Montgomery, Grant AU - Montgomery G AUID- ORCID: 0000-0002-4140-8139 AD - Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia. FAU - Zakrzewski, Martha AU - Zakrzewski M AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. FAU - Simms, Lisa A AU - Simms LA AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. FAU - Krishnaprasad, Krupa AU - Krishnaprasad K AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. FAU - Hanigan, Katherine AU - Hanigan K AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. FAU - Doecke, James D AU - Doecke JD AUID- ORCID: 0000-0003-2863-0293 AD - Australian eHealth Research Centre, CSIRO, Brisbane, QLD, Australia. FAU - Walsh, Alissa AU - Walsh A AD - Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, UK. FAU - Lawrance, Ian C AU - Lawrance IC AD - Centre of Inflammatory Bowel Diseases, Saint John of God Hospital Subiaco, University of Western Australia, WA, Australia. FAU - Bampton, Peter A AU - Bampton PA AD - Flinders Medical Centre, Adelaide, SA, Australia. FAU - Andrews, Jane M AU - Andrews JM AD - Department of Gastroenterology and Hepatology, Royal Adelaide Hospital & University of Adelaide, Adelaide, SA, Australia. FAU - Mahy, Gillian AU - Mahy G AD - Department of Gastroenterology and Hepatology, Townsville University Hospital, Townsville, QLD, Australia. FAU - Connor, Susan J AU - Connor SJ AUID- ORCID: 0000-0001-5606-0270 AD - Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, NSW, Australia. AD - South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia. FAU - Sparrow, Miles P AU - Sparrow MP AD - Department of Gastroenterology, Alfred Health, Melbourne, VIC, Australia. FAU - Bell, Sally AU - Bell S AD - Department of Gastroenterology and Hepatology, Monash Health, Melbourne, VIC, Australia. FAU - Florin, Timothy H AU - Florin TH AD - Inflammatory Bowel Diseases Group, Translational Research Institute, Brisbane, QLD, Australia. AD - Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. FAU - Begun, Jakob AU - Begun J AUID- ORCID: 0000-0001-5256-7672 AD - Inflammatory Bowel Diseases Group, Translational Research Institute, Brisbane, QLD, Australia. AD - Inflammatory Disease Biology and Therapeutics Group, Translational Research Institute, Brisbane, QLD, Australia. AD - Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. FAU - Gearry, Richard B AU - Gearry RB AD - Department of Medicine, University of Otago, Christchurch, New Zealand. FAU - Radford-Smith, Graham L AU - Radford-Smith GL AUID- ORCID: 0000-0002-2047-6239 AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. AD - Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. AD - Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. LA - eng GR - APP1028569/National Health and Medical Research Council/ GR - Royal Brisbane and Women's Hospital Foundation/ PT - Journal Article PL - England TA - J Crohns Colitis JT - Journal of Crohn's & colitis JID - 101318676 SB - IM MH - Humans MH - *Colitis, Ulcerative/genetics MH - Genome-Wide Association Study MH - Genetic Heterogeneity MH - Genetic Predisposition to Disease MH - Phenotype MH - Polymorphism, Single Nucleotide MH - Case-Control Studies PMC - PMC10024548 OTO - NOTNLM OT - Ulcerative colitis OT - disease severity OT - genetics COIS- The authors have no conflicts of interest to declare. EDAT- 2022/09/17 06:00 MHDA- 2023/03/22 06:00 PMCR- 2022/09/16 CRDT- 2022/09/16 08:42 PHST- 2022/09/17 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2022/09/16 08:42 [entrez] PHST- 2022/09/16 00:00 [pmc-release] AID - 6701957 [pii] AID - jjac121 [pii] AID - 10.1093/ecco-jcc/jjac121 [doi] PST - ppublish SO - J Crohns Colitis. 2023 Mar 18;17(2):277-288. doi: 10.1093/ecco-jcc/jjac121.