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Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis. Inflamm Bowel Dis 2018 03 19;24(4):829-838

Date

03/22/2018

Pubmed ID

29562276

Pubmed Central ID

PMC6350448

DOI

10.1093/ibd/izx084

Scopus ID

2-s2.0-85044446552   9 Citations

Abstract

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.

Author List

Venkateswaran S, Prince J, Cutler DJ, Marigorta UM, Okou DT, Prahalad S, Mack D, Boyle B, Walters T, Griffiths A, Sauer CG, LeLeiko N, Keljo D, Markowitz J, Baker SS, Rosh J, Pfefferkorn M, Heyman MB, Patel A, Otley A, Baldassano R, Noe J, Rufo P, Oliva-Hemker M, Davis S, Zwick ME, Gibson G, Denson LA, Hyams J, Kugathasan S

Author

Joshua D. Noe MD Associate Dean, Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Alleles
Case-Control Studies
Child
Child, Preschool
Colitis, Ulcerative
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA-DRB1 Chains
Humans
Male
Polymorphism, Single Nucleotide
United Kingdom