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J Crohns Colitis. 2018 Jun 13. doi: 10.1093/ecco-jcc/jjy080. [Epub ahead of print]

An intergenic variant rs9268877 between HLA-DRA and HLA-DRB contributes to the clinical course and long-term outcome of ulcerative colitis.

Author information

1
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
2
Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
3
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
4
Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
5
Department of Convergence Medicine, University of Ulsan College of Medicine & Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
6
Human Genetics Group, Genome Institute of Singapore, Singapore.
7
Saw Swee Hock School of Public Health,National University of Singapore, Singapore.
8
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
9
The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

Abstract

Background and Aims:

The genetic contribution to the prognosis of ulcerative colitis (UC) is poorly understood, and most currently known susceptibility loci are not associated with prognosis. To identify genetic variants influencing the prognosis of UC, we performed an Immunochip-based study using an extreme phenotype approach.

Methods:

Based on the finding that the only association Pdiscovery-meta < 1 × 10-4 was located in the human leukocyte antigen (HLA), we focused our analyses on the HLA region. We performed the analysis using HLA imputation data from three independent discovery cohorts of 607 UC patients (243 poor-prognosis and 364 good-prognosis), followed by replication in 274 UC patients (145 poor-prognosis and 129 good-prognosis).

Results:

We found that rs9268877, located between HLA-DRA and HLA-DRB, was associated with poor prognosis of UC at genome-wide significance (odds ratio [ORdiscovery] = 1.82; ORreplication = 1.55; ORcombined-meta = 1.72, Pcombined-meta = 1.04 × 10-8), with effect size (OR) increasing incrementally according to worsening of prognosis in each of the three independent discovery cohorts and the replication cohort. However, rs9268877 showed no association with UC susceptibility (ORcombined-meta = 1.07, Pcombined-meta = 0.135). rs9268877 influenced 30 year clinical outcomes, and the presence of the rs9268877 risk allele had a sensitivity of 80.0% and specificity of 38.1% for colectomy.

Conclusions:

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.

PMID:
29905830
DOI:
10.1093/ecco-jcc/jjy080

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