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Twin and Family Risk from Environment and Epigenetics (FREE) Studies Reveal Strong Environmental and Weaker Genetic Cues That Explain High Heritability of Eosinophilic Esophagitis

Alexander, Eileen Steinle, M.S.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900643

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Epidemiology (Environmental Health).
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. This work was developed to meet the needs of families affected by eosinophilic esophagitis, who asked, “Will my next child have EoE?” Objectives: 1) recruit two study groups: a nuclear family group and twin registry and their first degree relations, collect data and samples, create database, design, analyze and fund family-based studies, 2) quantify risk associated with genes and environment on familial clustering of EoE, and 3) explore and direct new lines of EoE and family-based research, including epigenetic mechanisms and environmental factors, for EoE and related immunologic conditions. The long-term objective is to mitigate risk for families with underlying genetic susceptibility by reducing exposure effects. 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. DNA collected from twins was analyzed using the Illumina 450Human Methylation array. Results: Analysis of the Nuclear-Family–based cohort revealed the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted), 2.3% (sex-adjusted), RRRs ranged from 10-64, depending on 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. EoE risk 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, genetic heritability was 14.5±4.0% (p<0.001); 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 differences in birth-weight were associated with disease discordance in twin pairs (p=0.01;n=35). Birth season was significantly different in concordant and discordant twin pairs (p=0.03;n=63); specifically, birth in Fall was associated with EoE discordance (p=0.02;n=63). Food allergies (p<0.001;n=97) and penicillin allergies (p=0.17; n=66) were associated with EoE. Breastfeeding (p=0.15;n=59) may reduce risk for EoE. Epigenetic methylation screen of effect size =5% difference between affected and unaffected monozygotic twins revealed 349 sites of interest, including candidate and novel genes. Conclusions: EoE recurrence risk ratios are increased 10 to 64-fold compared to population prevalence. 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%). The risk of having a second child with EoE is 2.4%. Common family environment (81.0%) and additive genetic heritability (14.5%) explain familial clustering. Early environmental modification may lessen EoE risks. Importantly, epigenetic methylation associated with EoE suggests novel mechanisms and genes. Familial clustering is largely attributable to common environmental exposures, suggesting that identifying modifiable common family environmental factors, in genetically susceptible individuals and families, particularly in early life, may mitigate risk.
Lisa Martin, Ph.D. (Committee Chair)
Paul Succop, Ph.D. (Committee Chair)
Vincent A. Mukkada, M.D. (Committee Member)
Margaret H. Collins, M.D. (Committee Member)
Erin Haynes, Dr.P.H. (Committee Member)
229 p.
Environmental Health
eosinophilia; medical genetics; twin and family-based; environment; gastrointestinal diseases; epigenetic methylation

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Citations

  • Alexander, E. S. (2014). Twin and Family Risk from Environment and Epigenetics (FREE) Studies Reveal Strong Environmental and Weaker Genetic Cues That Explain High Heritability of Eosinophilic Esophagitis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900643

    APA Style (7th edition)

  • Alexander, Eileen. Twin and Family Risk from Environment and Epigenetics (FREE) Studies Reveal Strong Environmental and Weaker Genetic Cues That Explain High Heritability of Eosinophilic Esophagitis. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900643.

    MLA Style (8th edition)

  • Alexander, Eileen. "Twin and Family Risk from Environment and Epigenetics (FREE) Studies Reveal Strong Environmental and Weaker Genetic Cues That Explain High Heritability of Eosinophilic Esophagitis." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900643

    Chicago Manual of Style (17th edition)

ucin1406900643
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© 2014, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.