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Genetic dissection of eosinophilic esophagitis provides insight into disease pathogenesis and treatment strategies

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Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus that is compounded by both genetic predisposition and aberrant responses to environmental antigens, particularly those that are food derived. Data have indicated a unique transcriptional response in vivo that defines EoE and that appears to be partially attributable to the TH2 cytokine IL-13. Moreover, a number of genetic risk variants in proinflammatory and epithelial cell genes associate with EoE susceptibility, demonstrating novel heritable mechanisms that contribute to disease risk. Here we discuss recent advances in our understanding of the intrinsic (genetic) and extrinsic (environmental) components that illustrate the complex nature of EoE.

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Epidemiology

With the expansion of EoE cases reported worldwide, multiple studies have aimed to establish a baseline prevalence of EoE and determine whether disease incidence has increased. From 2000-2003, the estimated prevalence of EoE in a pediatric population was approximately 4 in 10,000, with an incidence rate of 0.9 to 1.3 in 10,000 new cases per year.5 A similar prevalence (approximately 2 cases per 10,000) and incidence rate (1.4 per 100,000) during a 16-year period were observed in an adult Swiss

Genetic heritability

An underlying genetic predisposition to EoE has been proposed by multiple groups that show a disproportionate prevalence of disease in white subjects and male subjects and within families of affected subjects.15, 23 For instance, data over a 14-year period demonstrated that 90% of the patients with EoE were white and 75% were male.15 Reports of a familial occurrence of EoE and esophageal dilatation in 6.8% and 9.7% of patients with EoE, respectively, suggest that the prevalence of EoE and

Transcriptome analysis

A major step toward the molecular mapping of EoE was achieved when gene expression profiling of patients’ esophageal biopsy specimens showed a remarkable transcript signature that distinguishes patients with EoE from healthy control subjects and patients with chronic esophagitis.27 Altered expression of approximately 574 genes comprises this EoE “transcriptome,” which exhibits a high level of conservation among patients’ sex, age, and atopic history and strongly correlates with esophageal

Genetic variants and disease susceptibility

The number of studies investigating genetic variants associated with EoE are few compared with those for other more common and more widely recognized atopic diseases, such as AD and asthma. Regardless, there have been significant strides in uncovering EoE risk variants in a relatively short period of time14, 27, 52, 53 due in part to the technological advances in genotyping single nucleotide polymorphisms (SNPs) in large case-control cohorts. In all, there have been 4 candidate gene studies

Conclusions and future directions

In just over 10 years since the recognition of EoE as a distinct inflammatory disorder, the rapid progress toward characterizing the disease on multiple fronts has underscored its complexity. We now have insight into the natural history of EoE, its strong association with specific ethnicities and sexes, the genetic and environmental factors involved, and the molecular pathogenesis of the disease (Fig 1). Moreover, the burst of data illustrating EoE risk variants in CCL26, TGFB1, TSLP and CRLF2,

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    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Supported in part by National Institutes of Health (NIH) grants 2U19 AI066738, U19 AI070235, R01 DK076893, and R37 AI1045898; PHS Grant P30 DK078392; the Department of Defense; the Food Allergy Project; the Buckeye Foundation; and the Campaign Urging Research for Eosinophilic Disease (CURED) Foundation. J.D.S. is supported by a T32 NIH training grant (HL091805).

    Terms in boldface and italics are defined in the glossary on page 24.

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