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

Eileen S Alexander; Lisa J Martin; Margaret H Collins; Leah C Kottyan; Heidi Sucharew; Hua He; Vincent A Mukkada; Paul A Succop; J Pablo Abonia; Heather Foote; Michael D Eby; Tommie M Grotjan; Alexandria J Greenler; Evan S Dellon; Jeffrey G Demain; Glenn T Furuta; Larry E Gurian; John B Harley; Russell J Hopp; Amir Kagalwalla; Ajay Kaul; Kari C Nadeau; Richard J Noel; Philip E Putnam; Karl F von Tiehl; Marc E Rothenberg

doi:10.1016/j.jaci.2014.07.021

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

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

Authors

Eileen S Alexander¹, Lisa J Martin², Margaret H Collins², Leah C Kottyan², Heidi Sucharew², Hua He³, Vincent A Mukkada², Paul A Succop⁴, J Pablo Abonia², Heather Foote³, Michael D Eby³, Tommie M Grotjan³, Alexandria J Greenler³, Evan S Dellon⁵, Jeffrey G Demain⁶, Glenn T Furuta⁷, Larry E Gurian⁸, John B Harley⁹, Russell J Hopp¹⁰, Amir Kagalwalla¹¹, Ajay Kaul², Kari C Nadeau¹², Richard J Noel¹³, Philip E Putnam², Karl F von Tiehl¹⁴, Marc E Rothenberg¹⁵

Affiliations

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: [email protected].

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.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Twin Study

MeSH terms

Adolescent
Adult
Case-Control Studies
Child
Child, Preschool
Eosinophilic Esophagitis* / epidemiology
Eosinophilic Esophagitis* / genetics
Eosinophilic Esophagitis* / immunology
Family*
Female
Gene-Environment Interaction*
Humans
Infant
Male
Middle Aged
Risk Factors
Sex Factors
Twins, Dizygotic*
Twins, Monozygotic*

Abstract

Publication types

MeSH terms

Grants and funding