An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis
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Abstract
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 × 10−9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10−19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10−6]. No SNPs reached significance in the non-MRUC–control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 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.
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Studies indicate significant differences in SNPs associated with medically refractory ulcerative colitis compared to non-medically refractory ulcerative colitis.
“Studies indicate significant differences in SNPs associated with MRUC compared to non- MRUC[19], but translating these findings into practical screening protocols requires further validation.”
From Evaluating genetic insights into ulcerative colitis and anxiety: Limitations and future directions (2024) · cites this paper as [19]
Some genetic variants are linked to disease severity in ulcerative colitis.
“Moreover, research on prognosis in UC associated with Mendelian traits suggests that while some genetic variants are linked to disease severity, such as the SNPs identified in medically refractory UC (MRUC) studies[19], a comprehensive understanding of their prognostic value in routine clinical practice is still developing.”
From Evaluating genetic insights into ulcerative colitis and anxiety: Limitations and future directions (2024) · cites this paper as [19]
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Evaluating genetic insights into ulcerative colitis and anxiety: Limitations and future directions
Peng, Y., & Long, X.-D. (2024) · World Journal of Gastroenterology · doi:10.3748/wjg.v30.i37.4156 · Cited by 2 · see citing works
- Authors
- Mortlock, S., Lord, A., Montgomery, G., Zakrzewski, M., Simms, L. A., Krishnaprasad, K., Hanigan, K., Doecke, J. D., Walsh, A., Lawrance, I. C., Bampton, P. A., Andrews, J. M., Mahy, G., Connor, S. J., Sparrow, M. P., Bell, S., Florin, T. H., Begun, J., Gearry, R. B., & Radford-Smith, G. L.
- Affiliations
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- John Radcliffe Hospital (GB)
- St John of God Subiaco Hospital (AU)
- Flinders Medical Centre (AU)
- Royal Adelaide Hospital (AU)
- Townsville Hospital (AU)
- Liverpool Hospital (AU)
- The Alfred Hospital (AU)
- Monash Health (AU)
- Translational Research Institute (AU)
- University of Otago (NZ)
- QIMR Berghofer Medical Research Institute , Brisbane, QLD , Australia
- ORCID
- Venue
- Journal of Crohn's and Colitis
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-09-16
- Volume
- 17
- Issue
- 2
- Pages
- 277-288
- ISSN
- 1873-9946 (ISSN-L)
- 1876-4479
- PMC
- PMC10024548
- OpenAlex
- W4296033383
- Cited by
- 12
- References
- 54
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 2
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Crohn s and Colitis (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
- Funders
- National Health and Medical Research Council (APP1028569)
- Royal Brisbane and Women’s Hospital Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- ulcerative colitis
- MeSH terms
- Colitis, Ulcerative, Humans, Phenotype, Case-Control Studies, Genetic Heterogeneity, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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