title: Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.
abstract: BACKGROUND
  Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown.
  
  
  OBJECTIVE
  To quantify the risk associated with genes and environment on familial clustering of EoE.
  
  
  METHODS
  Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined.
  
  
  RESULTS
  Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% (P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% (P < .001), and common family environment contributed 81.0% ± 4% (P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status.
  
  
  CONCLUSIONS
  EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Health Services Administration, Xavier University, Cincinnati, Ohio.
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Alexander
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Heidi
authors.initials: H
authors.lastname: Sucharew
authors.affiliation: Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Mukkada
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Succop
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Abonia
authors.affiliation: Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Heather
authors.initials: H
authors.lastname: Foote
authors.affiliation: Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Eby
authors.affiliation: Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Tommie M
authors.initials: TM
authors.lastname: Grotjan
authors.affiliation: Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Alexandria J
authors.initials: AJ
authors.lastname: Greenler
authors.affiliation: Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Dellon
authors.affiliation: Allergy, Asthma and Immunology Center of Alaska, Anchorage, Alaska.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Demain
authors.affiliation: Gastrointestinal Eosinophilic Diseases Program, Children's Hospital Colorado, Digestive Health Institute, University of Colorado School of Medicine, Aurora, Colo.
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
authors.affiliation: Ferrell Duncan Clinic and CoxHealth, Springfield, Mo.
authors.forename: Larry E
authors.initials: LE
authors.lastname: Gurian
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; US Department of Veterans Affairs Medical Center, Cincinnati, Ohio.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Creighton University, Omaha, Neb.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Hopp
authors.affiliation: Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill; Northwestern University-Feinberg School of Medicine, Chicago, Ill.
authors.forename: Amir
authors.initials: A
authors.lastname: Kagalwalla
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kaul
authors.affiliation: Stanford Medical School, Stanford, Calif; Division of Allergy and Immunology, Stanford Medical Center and Lucille Packard Children's Hospital, Stanford, Calif.
authors.forename: Kari C
authors.initials: KC
authors.lastname: Nadeau
authors.affiliation: Children's Hospital of Wisconsin, Milwaukee, Wis; Medical College of Wisconsin, Milwaukee, Wis.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Noel
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Putnam
authors.affiliation: BowTie Allergy Specialists, Huntington Memorial Hospital, Pasadena, Calif.
authors.forename: Karl F
authors.initials: KF
authors.lastname: von Tiehl
authors.affiliation: Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Rothenberg@cchmc.org.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D057765:Eosinophilic Esophagitis / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D005190:Family; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012737:Sex Factors; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
keywords: Eosinophilia; drug hypersensitivity; food allergy; gastrointestinal diseases; gene-environment interaction; heritability; immune system diseases; medical genetics; skin diseases; twins