PMID- 29562276 OWN - NLM STAT- MEDLINE DCOM- 20190523 LR - 20210109 IS - 1536-4844 (Electronic) IS - 1078-0998 (Print) IS - 1078-0998 (Linking) VI - 24 IP - 4 DP - 2018 Mar 19 TI - Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis. PG - 829-838 LID - 10.1093/ibd/izx084 [doi] AB - 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. FAU - Venkateswaran, Suresh AU - Venkateswaran S AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA. FAU - Prince, Jarod AU - Prince J AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA. FAU - Cutler, David J AU - Cutler DJ AD - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA. FAU - Marigorta, Urko M AU - Marigorta UM AD - Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA. FAU - Okou, David T AU - Okou DT AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA. FAU - Prahalad, Sampath AU - Prahalad S AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA. FAU - Mack, David AU - Mack D AD - Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, Ontario, Canada. FAU - Boyle, Brendan AU - Boyle B AD - Department of Gastroenterology, Nationwide Children's Hospital Columbus, OH. FAU - Walters, Thomas AU - Walters T AD - Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada. FAU - Griffiths, Anne AU - Griffiths A AD - Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada. FAU - Sauer, Cary G AU - Sauer CG AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA. FAU - LeLeiko, Neal AU - LeLeiko N AD - Division of Pediatric Gastroenterology, Nutrition, and Liver Diseases, Hasbro Children's Hospital, Providence, RI. FAU - Keljo, David AU - Keljo D AD - Gastroenterology, Hepatology and Nutrition Department, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA. FAU - Markowitz, James AU - Markowitz J AD - Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cohen Children's Medical Center of NY, New Hyde Park, NY. FAU - Baker, Susan S AU - Baker SS AD - Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, NY. FAU - Rosh, Joel AU - Rosh J AD - Department of Pediatrics, Goryeb Children's Hospital, Morristown, NJ. FAU - Pfefferkorn, Marian AU - Pfefferkorn M AD - Bronson Pediatric Gastroenterology, Bronson Children's Hospital, Kalamazoo, MI. FAU - Heyman, Melvin B AU - Heyman MB AD - Department of Pediatrics, University of California at San Francisco, San Francisco, CA. FAU - Patel, Ashish AU - Patel A AD - Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Otley, Anthony AU - Otley A AD - Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Baldassano, Robert AU - Baldassano R AD - Department of Pediatrics, University of Pennsylvania, Philadelphia, PA. FAU - Noe, Joshua AU - Noe J AD - Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI. FAU - Rufo, Paul AU - Rufo P AD - Division of Gastroenterology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA. FAU - Oliva-Hemker, Maria AU - Oliva-Hemker M AD - Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, MD. FAU - Davis, Sonia AU - Davis S AD - Collaborative Studies Coordinating Center Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC. FAU - Zwick, Michael E AU - Zwick ME AD - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA. FAU - Gibson, Greg AU - Gibson G AD - Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA. FAU - Denson, Lee A AU - Denson LA AD - Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. FAU - Hyams, Jeffrey AU - Hyams J AD - Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT. FAU - Kugathasan, Subra AU - Kugathasan S AD - Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom GR - P30 DK078392/DK/NIDDK NIH HHS/United States GR - R01 DK087694/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Inflamm Bowel Dis JT - Inflammatory bowel diseases JID - 9508162 RN - 0 (HLA-DRB1 Chains) RN - Pediatric ulcerative colitis SB - IM MH - Adolescent MH - Alleles MH - Case-Control Studies MH - Child MH - Child, Preschool MH - Colitis, Ulcerative/*genetics MH - Female MH - *Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - HLA-DRB1 Chains/*genetics MH - Humans MH - Male MH - Polymorphism, Single Nucleotide MH - United Kingdom PMC - PMC6350448 EDAT- 2018/03/22 06:00 MHDA- 2019/05/24 06:00 PMCR- 2019/03/19 CRDT- 2018/03/22 06:00 PHST- 2018/03/22 06:00 [entrez] PHST- 2018/03/22 06:00 [pubmed] PHST- 2019/05/24 06:00 [medline] PHST- 2019/03/19 00:00 [pmc-release] AID - 4944340 [pii] AID - izx084 [pii] AID - 10.1093/ibd/izx084 [doi] PST - ppublish SO - Inflamm Bowel Dis. 2018 Mar 19;24(4):829-838. doi: 10.1093/ibd/izx084.