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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

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

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%).

KEYWORDS:

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

PMID:
25258143
PMCID:
PMC4253562
DOI:
10.1016/j.jaci.2014.07.021
[Indexed for MEDLINE]
Free PMC Article

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