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J Allergy Clin Immunol. 2014 Nov;134(5):1084-1092.e1. doi: 10.1016/j.jaci.2014.07.021. Epub 2014 Sep 22.

Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.

Author information

  • 1Departments 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.
  • 2Departments 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.
  • 3Divisions 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.
  • 4Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 5Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC.
  • 6Allergy, Asthma and Immunology Center of Alaska, Anchorage, Alaska.
  • 7Gastrointestinal Eosinophilic Diseases Program, Children's Hospital Colorado, Digestive Health Institute, University of Colorado School of Medicine, Aurora, Colo.
  • 8Ferrell Duncan Clinic and CoxHealth, Springfield, Mo.
  • 9Departments 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.
  • 10Division of Allergy and Immunology, Department of Pediatrics, Creighton University, Omaha, Neb.
  • 11Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill; Northwestern University-Feinberg School of Medicine, Chicago, Ill.
  • 12Stanford Medical School, Stanford, Calif; Division of Allergy and Immunology, Stanford Medical Center and Lucille Packard Children's Hospital, Stanford, Calif.
  • 13Children's Hospital of Wisconsin, Milwaukee, Wis; Medical College of Wisconsin, Milwaukee, Wis.
  • 14BowTie Allergy Specialists, Huntington Memorial Hospital, Pasadena, Calif.
  • 15Departments 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.

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%).

Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.

KEYWORDS:

Eosinophilia; drug hypersensitivity; food allergy; gastrointestinal diseases; gene-environment interaction; heritability; immune system diseases; medical genetics; skin diseases; twins

PMID:
25258143
[PubMed - indexed for MEDLINE]
PMCID:
PMC4253562
Free PMC Article
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