Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis

Venkateswaran S1, Prince J1, Cutler DJ2, Marigorta UM3, Okou DT1, Prahalad S1, Mack D4, Boyle B5, Walters T6, Griffiths A6, Sauer CG1, LeLeiko N7, Keljo D8, Markowitz J9, Baker SS10, Rosh J11, Pfefferkorn M12, Heyman MB13, Patel A14, Otley A15, Baldassano R16, Noe J17, Rufo P18, Oliva-Hemker M19, Davis S20, Zwick ME2, Gibson G3, Denson LA21, Hyams J22, Kugathasan S1. Inflamm Bowel Dis. 2018 Mar 19;24(4):829-838. doi: 10.1093/ibd/izx084.

Author information

1 Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA.

2 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA.

3 Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA.

4 Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ontario, Canada.

5 Department of Gastroenterology, Nationwide Children's Hospital Columbus, OH.

6 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

7 Division of Pediatric Gastroenterology, Nutrition, and Liver Diseases, Hasbro Children's Hospital, Providence, RI.

8 Gastroenterology, Hepatology and Nutrition Department, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.

9 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cohen Children's Medical Center of NY, New Hyde Park, NY.

10 Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, NY.

11 Department of Pediatrics, Goryeb Children's Hospital, Morristown, NJ.

12 Bronson Pediatric Gastroenterology, Bronson Children's Hospital, Kalamazoo, MI.

13 Department of Pediatrics, University of California at San Francisco, San Francisco, CA.

14 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.

15 Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.

16 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA.

17 Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI.

18 Division of Gastroenterology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA.

19 Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, MD.

20 Collaborative Studies Coordinating Center Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

21 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

22 Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT.


BACKGROUND: The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59).

METHOD: To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC.

RESULTS: HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease(E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13).

CONCLUSION: In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

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