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 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 the new 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 10–64, depending on the family relationship, and were higher in brothers (64.0; p=0.04), fathers (42.9; p=0.004) and males (50.7; p<0.001) compared to sisters, mothers and females, respectively. Risk of EoE for other siblings was 2.4%. In the Nuclear-Families, combined gene and common environment heritability (hgc2) was 72.0±2.7% (p<0.001). In the Twins cohort, genetic heritability was 14.5±4.0% (p<0.001), and common family environment contributed 81.0±4% (p<0.001) to phenotypic variance. Proband-wise concordance in MZ co-twins was 57.9±9.5% compared to 36.4±9.3% in DZ (p=0.11). Greater birth-weight difference between twins (p=0.01), breastfeeding (p=0.15) and Fall birth season (p=0.02) were associated with twin discordance in disease status. Conclusions EoE recurrence risk ratios are increased 10–64-fold compared with the general population. EoE in relatives is 1.8–2.4%, depending upon relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).

How I treat hypereosinophilic syndromes

“…47 In contrast, familial multisystem HES appears to be extremely rare. Autosomal dominant transmission of HE has been mapped to chromosome 5q31-33 in one extended family.…”

Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity

“…IL-13 is thought to mediate these responses through epigenetic changes, including elevated levels of histone acetylation and decreased DNA methylation in the promoters of critical mediators, such as eotaxin 3 (also known as CCL26), CAPN14, and NTRK1 (14)(15)(16). Co-occurrence of epigenetic changes with transcriptional response suggests that integrating transcriptional and epigenetic analyses may serve as a useful approach to discover molecules with functional roles in EoE pathogenesis, especially since EoE is influenced by gene-environment interactions (17).…”

Eosinophilic esophagitis: New insights in pathogenesis and therapy

“…This latter low incidence suggests a strong environmental contribution to acquiring this disease. This conclusion is supported by the finding that although the nuclear-family heritability appeared to be high (72.0%), the twins cohort analysis revealed that this high levels are likely due to a powerful role of a common environment that occurs in 81.0% of the cases [45] .…”