An Intergenic Variant rs9268877 Between HLA-DRA and HLA-DRB Contributes to the Clinical Course and Long-term Outcome of Ulcerative Colitis

Lee, Ho‐Su; Yang, Suk Kyun; Hong, Myunghee; Jung, Seulgi; Kim, Byoung Mok; Moon, Jung Won; Park, Sang Hyoung; Ye, Byong Duk; Oh, Seak Hee; Kim, Kyung Mo; Yoon, Yong Sik; Yu, Chang Sik; Baek, Jiwon; Lee, Cue Hyunkyu; Han, Buhm; Liu, Jing; Haritunians, Talin; McGovern, Dermot; Song, Kyuyoung

doi:10.1093/ecco-jcc/jjy080

Cited by 12 publications

(15 citation statements)

References 38 publications

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“…Genetic and environmental factors may play roles. Although the genetic associations for UC overlap more extensively between Asian patients and patients of European ancestry than those for CD, the difference in the clinical course between these populations is more prominent in UC than in CD 30. However, this does not necessarily indicate that environmental factors are more important than genetic factors in determining the prognosis of UC versus that of CD.…”

Section: Discussionmentioning

confidence: 95%

“…Even among East Asians, the proportion of proctitis is higher in Koreans than in Chinese 6 12. With respect to the genetic predictors of UC prognosis, the intergenic variant rs9268877 between HLA-DRA and HLA-DRB has been reported to be associated with a poor prognosis of UC in Koreans 30. However, this association is yet to be reported in other Asian populations.…”

Section: Discussionmentioning

confidence: 98%

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Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea

Myung

Park

Rhee

et al. 2019

Gut

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ObjectiveNo population-based study has evaluated the natural course of UC over three decades in non-Caucasians. We aimed to assess the long-term natural course of Korean patients with UC in a population-based cohort.DesignThis Korean population-based, Songpa-Kangdong IBD cohort included all patients (n=1013) newly diagnosed with UC during 1986–2015. Disease outcomes and their predictors were evaluated.ResultsDuring the median follow-up of 105 months, the overall use of systemic corticosteroids, thiopurines and antitumour necrosis factor (anti-TNF) agents was 40.8%, 13.9% and 6.5%, respectively. Over time, the cumulative risk of commencing corticosteroids decreased, whereas that of commencing thiopurines and anti-TNF agents increased. During follow-up, 28.7% of 778 patients with proctitis or left-sided colitis at diagnosis experienced proximal disease extension. A total of 28 patients (2.8%) underwent colectomy, demonstrating cumulative risks of colectomy at 1, 5, 10, 20 and 30 years after diagnosis of 1.0%, 1.9%, 2.2%, 5.1% and 6.4%, respectively. Multivariate Cox regression analysis revealed that extensive colitis at diagnosis (HR 8.249, 95% CI 2.394 to 28.430), ever use of corticosteroids (HR 6.437, 95% CI 1.440 to 28.773) and diagnosis in the anti-TNF era (HR 0.224, 95% CI 0.057 to 0.886) were independent predictors of colectomy. The standardised mortality ratio in patients with UC was 0.725 (95% CI 0.508 to 1.004).ConclusionKorean patients with UC may have a better clinical course than Western patients, as indicated by a lower colectomy rate. The overall colectomy rate has continued to decrease over the past three decades.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea

Myung

Park

Rhee

et al. 2019

Gut

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“…A recent Korean study identified HLA‐DRB4*01:01 as a risk genotype for ulcerative colitis, however this allele was in strong linkage disequilibrium with a SNP, rs9268877, lying between the HLA‐DRA and DRB genes . Following correction for this genotype, rs9268877 was the strongest risk signal and conferred an increased risk of severe disease with poor outcome (OR 1.72) …”

Section: Specific Associations: Hla and Ibdmentioning

confidence: 99%

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Ashton

Latham

Beattie

et al. 2019

Aliment Pharmacol Ther

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Summary Background The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome‐wide association studies (GWAS). Aims To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. Methods An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. Results All classical HLA genes with variation (including HLA‐A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD‐associated genotypes. The most implicated gene is HLA‐DRB1, with HLA‐DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti‐TNF agents (antibody formation). Conclusions The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long‐read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

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“…Using a similar approach, Kopylov et al found that none of their studied susceptibility loci were associated with benign UC [44]. In East Asians with UC, the SNP located between HLA-DRA and HLA-DRB (rs9268877) was found to be associated with a poor prognosis but not with susceptibility [45]. These studies highlight the need for detailed clinically relevant sub-phenotypes and categorization by relevant clinical outcomes in IBD.…”

Section: The Predictability Of Ibd Disease Progressionmentioning

confidence: 99%

“…Although IBD patients tend to have larger average PRS than non-IBD individuals, this has not produced substantial improvements in predicting their clinical course. Indeed, no associations could be shown between genetic burden and development of complicated disease or need for surgery [39,42,44,45,46,47].…”

Section: The Predictability Of Ibd Disease Progressionmentioning

confidence: 99%

Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making?

Lee

Cleynen

2019

Cells

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Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches.

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An Intergenic Variant rs9268877 Between HLA-DRA and HLA-DRB Contributes to the Clinical Course and Long-term Outcome of Ulcerative Colitis

Abstract: Our results provide new insights into prognosis-associated genetic variation in UC, which appears to be distinct from the genetic contribution to disease susceptibility. These findings could be useful in identifying poor-prognosis patients who might benefit from early aggressive therapy.

Cited by 12 publications

References 38 publications

Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea

Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making?

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