Leah C Kottyan1, Michael P Trimarchi2, Xiaoming Lu3, Julie M Caldwell2, Avery Maddox3, Sreeja Parameswaran3, Michael Lape4, Rahul J D'Mello5, Madeline Bonfield6, Adina Ballaban2, Vincent Mukkada7, Philip E Putnam7, Pablo Abonia8, Netali Ben-Baruch Morgenstern2, Amy A Eapen8, Ting Wen9, Matthew T Weirauch10, Marc E Rothenberg11. 1. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio. 2. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 4. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Graduate Program in Biomedical Informatics, University of Cincinnati, College of Medicine, Cincinnati, Ohio. 5. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Immunology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, Ohio. 6. Immunology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, Ohio. 7. Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 8. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 9. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio. 10. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 11. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio. Electronic address: rothenberg@cchmc.org.
Abstract
BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging, chronic, rare allergic disease associated with marked eosinophil accumulation in the esophagus. Previous genome-wide association studies have provided strong evidence for 3 genome-wide susceptibility loci. OBJECTIVE: We sought to replicate known and suggestive EoE genetic risk loci and conduct a meta-analysis of previously reported data sets. METHODS: An EoE-Custom single-nucleotide polymophism (SNP) Chip containing 956 candidate EoE risk single-nucleotide polymorphisms was used to genotype 627 cases and 365 controls. Statistical power was enhanced by adding 1959 external controls and performing meta-analyses with 2 independent EoE genome-wide association studies. RESULTS: Meta-analysis identified replicated association and genome-wide significance at 6 loci: 2p23 (2 independent genetic effects) and 5q22, 10p14, 11q13, and 16p13. Seven additional loci were identified at suggestive significance (P < 10-6): 1q31, 5q23, 6q15, 6q21, 8p21, 17q12, and 22q13. From these risk loci, 13 protein-coding EoE candidate risk genes were expressed in a genotype-dependent manner. EoE risk genes were expressed in disease-relevant cell types, including esophageal epithelia, fibroblasts, and immune cells, with some expressed as a function of disease activity. The genetic risk burden of EoE-associated genetic variants was markedly larger in cases relative to controls (P < 10-38); individuals with the highest decile of genetic burden had greater than 12-fold risk of EoE compared with those within the lowest decile. CONCLUSIONS: This study extends the genetic underpinnings of EoE, highlighting 13 genes whose genotype-dependent expression expands our etiologic understanding of EoE and provides a framework for a polygenic risk score to be validated in future studies.
BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging, chronic, rare allergic disease associated with marked eosinophil accumulation in the esophagus. Previous genome-wide association studies have provided strong evidence for 3 genome-wide susceptibility loci. OBJECTIVE: We sought to replicate known and suggestive EoE genetic risk loci and conduct a meta-analysis of previously reported data sets. METHODS: An EoE-Custom single-nucleotide polymophism (SNP) Chip containing 956 candidate EoE risk single-nucleotide polymorphisms was used to genotype 627 cases and 365 controls. Statistical power was enhanced by adding 1959 external controls and performing meta-analyses with 2 independent EoE genome-wide association studies. RESULTS: Meta-analysis identified replicated association and genome-wide significance at 6 loci: 2p23 (2 independent genetic effects) and 5q22, 10p14, 11q13, and 16p13. Seven additional loci were identified at suggestive significance (P < 10-6): 1q31, 5q23, 6q15, 6q21, 8p21, 17q12, and 22q13. From these risk loci, 13 protein-coding EoE candidate risk genes were expressed in a genotype-dependent manner. EoE risk genes were expressed in disease-relevant cell types, including esophageal epithelia, fibroblasts, and immune cells, with some expressed as a function of disease activity. The genetic risk burden of EoE-associated genetic variants was markedly larger in cases relative to controls (P < 10-38); individuals with the highest decile of genetic burden had greater than 12-fold risk of EoE compared with those within the lowest decile. CONCLUSIONS: This study extends the genetic underpinnings of EoE, highlighting 13 genes whose genotype-dependent expression expands our etiologic understanding of EoE and provides a framework for a polygenic risk score to be validated in future studies.
Authors: Michael S Benninger; Madeleine Strohl; Chantal E Holy; Andrea L Hanick; Paul C Bryson Journal: Int Forum Allergy Rhinol Date: 2017-06-14 Impact factor: 3.858
Authors: Benjamin P Davis; Emily M Stucke; M Eyad Khorki; Vladislav A Litosh; Jeffrey K Rymer; Mark Rochman; Jared Travers; Leah C Kottyan; Marc E Rothenberg Journal: JCI Insight Date: 2016-04
Authors: Xiaoming Lu; Erin E Zoller; Matthew T Weirauch; Zhiguo Wu; Bahram Namjou; Adrienne H Williams; Julie T Ziegler; Mary E Comeau; Miranda C Marion; Stuart B Glenn; Adam Adler; Nan Shen; Swapan K Nath; Anne M Stevens; Barry I Freedman; Betty P Tsao; Chaim O Jacob; Diane L Kamen; Elizabeth E Brown; Gary S Gilkeson; Graciela S Alarcón; John D Reveille; Juan-Manuel Anaya; Judith A James; Kathy L Sivils; Lindsey A Criswell; Luis M Vilá; Marta E Alarcón-Riquelme; Michelle Petri; R Hal Scofield; Robert P Kimberly; Rosalind Ramsey-Goldman; Young Bin Joo; Jeongim Choi; Sang-Cheol Bae; Susan A Boackle; Deborah Cunninghame Graham; Timothy J Vyse; Joel M Guthridge; Patrick M Gaffney; Carl D Langefeld; Jennifer A Kelly; Kenneth D Greis; Kenneth M Kaufman; John B Harley; Leah C Kottyan Journal: Am J Hum Genet Date: 2015-04-09 Impact factor: 11.025
Authors: Liming Liang; Nilesh Morar; Anna L Dixon; G Mark Lathrop; Goncalo R Abecasis; Miriam F Moffatt; William O C Cookson Journal: Genome Res Date: 2013-01-23 Impact factor: 9.043
Authors: Zubin H Patel; Xiaoming Lu; Daniel Miller; Carmy R Forney; Joshua Lee; Arthur Lynch; Connor Schroeder; Lois Parks; Albert F Magnusen; Xiaoting Chen; Mario Pujato; Avery Maddox; Erin E Zoller; Bahram Namjou; Hermine I Brunner; Michael Henrickson; Jennifer L Huggins; Adrienne H Williams; Julie T Ziegler; Mary E Comeau; Miranda C Marion; Stuart B Glenn; Adam Adler; Nan Shen; Swapan K Nath; Anne M Stevens; Barry I Freedman; Bernardo A Pons-Estel; Betty P Tsao; Chaim O Jacob; Diane L Kamen; Elizabeth E Brown; Gary S Gilkeson; Graciela S Alarcón; Javier Martin; John D Reveille; Juan-Manuel Anaya; Judith A James; Kathy L Sivils; Lindsey A Criswell; Luis M Vilá; Michelle Petri; R Hal Scofield; Robert P Kimberly; Jeffrey C Edberg; Rosalind Ramsey-Goldman; So-Young Bang; Hye-Soon Lee; Sang-Cheol Bae; Susan A Boackle; Deborah Cunninghame Graham; Timothy J Vyse; Joan T Merrill; Timothy B Niewold; Hannah C Ainsworth; Earl D Silverman; Michael H Weisman; Daniel J Wallace; Prithvi Raj; Joel M Guthridge; Patrick M Gaffney; Jennifer A Kelly; Marta E Alarcón-Riquelme; Carl D Langefeld; Edward K Wakeland; Kenneth M Kaufman; Matthew T Weirauch; John B Harley; Leah C Kottyan Journal: Hum Mol Genet Date: 2018-07-01 Impact factor: 5.121
Authors: Lavinia Paternoster; Marie Standl; Johannes Waage; Hansjörg Baurecht; Melanie Hotze; David P Strachan; John A Curtin; Klaus Bønnelykke; Chao Tian; Atsushi Takahashi; Jorge Esparza-Gordillo; Alexessander Couto Alves; Jacob P Thyssen; Herman T den Dekker; Manuel A Ferreira; Elisabeth Altmaier; Patrick Ma Sleiman; Feng Li Xiao; Juan R Gonzalez; Ingo Marenholz; Birgit Kalb; Maria Pino Yanes; Cheng-Jian Xu; Lisbeth Carstensen; Maria M Groen-Blokhuis; Cristina Venturini; Craig E Pennell; Sheila J Barton; Albert M Levin; Ivan Curjuric; Mariona Bustamante; Eskil Kreiner-Møller; Gabrielle A Lockett; Jonas Bacelis; Supinda Bunyavanich; Rachel A Myers; Anja Matanovic; Ashish Kumar; Joyce Y Tung; Tomomitsu Hirota; Michiaki Kubo; Wendy L McArdle; A J Henderson; John P Kemp; Jie Zheng; George Davey Smith; Franz Rüschendorf; Anja Bauerfeind; Min Ae Lee-Kirsch; Andreas Arnold; Georg Homuth; Carsten O Schmidt; Elisabeth Mangold; Sven Cichon; Thomas Keil; Elke Rodríguez; Annette Peters; Andre Franke; Wolfgang Lieb; Natalija Novak; Regina Fölster-Holst; Momoko Horikoshi; Juha Pekkanen; Sylvain Sebert; Lise L Husemoen; Niels Grarup; Johan C de Jongste; Fernando Rivadeneira; Albert Hofman; Vincent Wv Jaddoe; Suzanne Gma Pasmans; Niels J Elbert; André G Uitterlinden; Guy B Marks; Philip J Thompson; Melanie C Matheson; Colin F Robertson; Janina S Ried; Jin Li; Xian Bo Zuo; Xiao Dong Zheng; Xian Yong Yin; Liang Dan Sun; Maeve A McAleer; Grainne M O'Regan; Caoimhe Mr Fahy; Linda E Campbell; Milan Macek; Michael Kurek; Donglei Hu; Celeste Eng; Dirkje S Postma; Bjarke Feenstra; Frank Geller; Jouke Jan Hottenga; Christel M Middeldorp; Pirro Hysi; Veronique Bataille; Tim Spector; Carla Mt Tiesler; Elisabeth Thiering; Badri Pahukasahasram; James J Yang; Medea Imboden; Scott Huntsman; Natàlia Vilor-Tejedor; Caroline L Relton; Ronny Myhre; Wenche Nystad; Adnan Custovic; Scott T Weiss; Deborah A Meyers; Cilla Söderhäll; Erik Melén; Carole Ober; Benjamin A Raby; Angela Simpson; Bo Jacobsson; John W Holloway; Hans Bisgaard; Jordi Sunyer; Nicole M Probst Hensch; L Keoki Williams; Keith M Godfrey; Carol A Wang; Dorret I Boomsma; Mads Melbye; Gerard H Koppelman; Deborah Jarvis; Wh Irwin McLean; Alan D Irvine; Xue Jun Zhang; Hakon Hakonarson; Christian Gieger; Esteban G Burchard; Nicholas G Martin; Liesbeth Duijts; Allan Linneberg; Marjo-Riitta Jarvelin; Markus M Noethen; Susanne Lau; Norbert Hübner; Young-Ae Lee; Mayumi Tamari; David A Hinds; Daniel Glass; Sara J Brown; Joachim Heinrich; David M Evans; Stephan Weidinger Journal: Nat Genet Date: 2015-10-19 Impact factor: 38.330
Authors: Jamie Tanzer; Di Meng; Asa Ohsaki; Julie M Caldwell; Melissa K Mingler; Marc E Rothenberg; Michiko K Oyoshi Journal: PLoS One Date: 2022-06-27 Impact factor: 3.752
Authors: Thomas A E Platts-Mills; Behnam Keshavarz; Jeffrey M Wilson; Rung-Chi Li; Peter W Heymann; Diane R Gold; Emily C McGowan; Elizabeth A Erwin Journal: Children (Basel) Date: 2021-05-20