Suresh Venkateswaran1, Jarod Prince1, David J Cutler2, Urko M Marigorta3, David T Okou1, Sampath Prahalad1, David Mack4, Brendan Boyle5, Thomas Walters6, Anne Griffiths6, Cary G Sauer1, Neal LeLeiko7, David Keljo8, James Markowitz9, Susan S Baker10, Joel Rosh11, Marian Pfefferkorn12, Melvin B Heyman13, Ashish Patel14, Anthony Otley15, Robert Baldassano16, Joshua Noe17, Paul Rufo18, Maria Oliva-Hemker19, Sonia Davis20, Michael E Zwick2, Greg Gibson3, Lee A Denson21, Jeffrey Hyams22, Subra Kugathasan1. 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.
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.
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.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Jonathan Marchini; David Cutler; Nick Patterson; Matthew Stephens; Eleazar Eskin; Eran Halperin; Shin Lin; Zhaohui S Qin; Heather M Munro; Goncalo R Abecasis; Peter Donnelly Journal: Am J Hum Genet Date: 2006-01-26 Impact factor: 11.025
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Charlotte I de Bie; Stephan Buderus; Bhupinder K Sandhu; Lissy de Ridder; Anders Paerregaard; Gabor Veres; Jorge Amil Dias; Johanna C Escher Journal: J Pediatr Gastroenterol Nutr Date: 2012-03 Impact factor: 2.839
Authors: Soumya Raychaudhuri; Cynthia Sandor; Eli A Stahl; Jan Freudenberg; Hye-Soon Lee; Xiaoming Jia; Lars Alfredsson; Leonid Padyukov; Lars Klareskog; Jane Worthington; Katherine A Siminovitch; Sang-Cheol Bae; Robert M Plenge; Peter K Gregersen; Paul I W de Bakker Journal: Nat Genet Date: 2012-01-29 Impact factor: 38.330
Authors: Mark S Silverberg; Judy H Cho; John D Rioux; Dermot P B McGovern; Jing Wu; Vito Annese; Jean-Paul Achkar; Philippe Goyette; Regan Scott; Wei Xu; M Michael Barmada; Lambertus Klei; Mark J Daly; Clara Abraham; Theodore M Bayless; Fabrizio Bossa; Anne M Griffiths; Andrew F Ippoliti; Raymond G Lahaie; Anna Latiano; Pierre Paré; Deborah D Proctor; Miguel D Regueiro; A Hillary Steinhart; Stephan R Targan; L Philip Schumm; Emily O Kistner; Annette T Lee; Peter K Gregersen; Jerome I Rotter; Steven R Brant; Kent D Taylor; Kathryn Roeder; Richard H Duerr Journal: Nat Genet Date: 2009-01-04 Impact factor: 38.330
Authors: Jeffrey S Hyams; Sonia Davis Thomas; Nathan Gotman; Yael Haberman; Rebekah Karns; Melanie Schirmer; Angela Mo; David R Mack; Brendan Boyle; Anne M Griffiths; Neal S LeLeiko; Cary G Sauer; David J Keljo; James Markowitz; Susan S Baker; Joel Rosh; Robert N Baldassano; Ashish Patel; Marian Pfefferkorn; Anthony Otley; Melvin Heyman; Joshua Noe; Maria Oliva-Hemker; Paul A Rufo; Jennifer Strople; David Ziring; Stephen L Guthery; Boris Sudel; Keith Benkov; Prateek Wali; Dedrick Moulton; Jonathan Evans; Michael D Kappelman; M Alison Marquis; Francisco A Sylvester; Margaret H Collins; Suresh Venkateswaran; Marla Dubinsky; Vin Tangpricha; Krista L Spada; Bradley Saul; Jessie Wang; Jose Serrano; Kevin Hommel; Urko M Marigorta; Greg Gibson; Ramnik J Xavier; Subra Kugathasan; Thomas Walters; Lee A Denson Journal: Lancet Date: 2019-03-29 Impact factor: 79.321
Authors: Jeffrey S Hyams; Michael Brimacombe; Yael Haberman; Thomas Walters; Greg Gibson; Angela Mo; David Mack; Anne Griffiths; Brendan Boyle; Neal LeLeiko; James Markowitz; Joel Rosh; Ashish Patel; Sapana Shah; Robert Baldassano; Marian Pfefferkorn; Cary Sauer; Joelynn Dailey; Suresh Venkateswaran; Subra Kugathasan; Lee A Denson Journal: Inflamm Bowel Dis Date: 2022-02-01 Impact factor: 5.325