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

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% 6 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%).