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Genetic variations in the TLR3 locus are associated with eosinophilic esophagitis.

ABSTRACT: Eosinophilic esophagitis (EoE) is an antigen-driven disease mediated by an abnormal immune Th2 response.The objective of this article is to investigate genes associated with regulating immune responses leading to disease susceptibility.Twenty-seven tag single nucleotide polymorphisms (tSNPs) selected in five candidate genes (TLR3, TLR4, FOXP3, FLG and TSLP) were genotyped in 218 EoE patients and 376 controls. Skin prick tests were carried out in EoE patients with a panel of 17 aeroallergens and 22 plant- and animal-derived foods.Five tSNPs located in the TSLP locus and one tSNP located in the TLR3 locus were significantly associated with EoE. The interactions between TLR3 and TSLP loci were analyzed. TLR3+/TSLP- and TLR3-/TSLP+ individuals showed a significantly reduced susceptibility to EoE compared to TLR3-/TSLP- individuals (OR?=?0.66, p?=?0.036 and OR?=?0.23, p?=?0.00014, respectively). Likewise, TLR3+/TSLP+ individuals showed the most decreased susceptibility of developing EoE (OR?=?0.16, p?=?0.0001). However, the interaction gain attributed to the combination of both genes was negative (IG?=?-4.52%), which indicated redundancy or independent effect. Additionally, TLR3 locus was found to be associated with aeroallergen and food sensitization in EoE patients (OR?=?9.67, pc?=?0.025 and OR?=?0.53, pc?=?0.048, respectively).TLR3 constitutes a novel genetic susceptibility locus for developing EoE, and the effects would be independent of TSLP.

SUBMITTER: Avila-Castellano R

PROVIDER: S-EPMC5949969 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Genetic variations in the <i>TLR3</i> locus are associated with eosinophilic esophagitis.

Ávila-Castellano Robledo R García-Lozano José-Raúl JR Cimbollek Stefan S Lucendo Alfredo J AJ Bozada Juan-Manuel JM Quiralte Joaquín J

United European gastroenterology journal 20170913 3

<h4>Background</h4>Eosinophilic esophagitis (EoE) is an antigen-driven disease mediated by an abnormal immune Th2 response.<h4>Objective</h4>The objective of this article is to investigate genes associated with regulating immune responses leading to disease susceptibility.<h4>Methods</h4>Twenty-seven tag single nucleotide polymorphisms (tSNPs) selected in five candidate genes (<i>TLR3, TLR4, FOXP3, FLG</i> and <i>TSLP</i>) were genotyped in 218 EoE patients and 376 controls. Skin prick tests wer ...[more]

PMID: 29774148

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Project description:Background & aimsAn association of eosinophilic esophagitis (EoE) with esophageal dysmotility has been described, however, the related mechanism remains unclear. We aimed to evaluate clinical and physiologic characteristics, including esophageal distensibility, associated with secondary peristalsis in patients with EoE.MethodsA total of 199 consecutive adult patients with EoE (age, 18-78 y; 32% female) who completed a 16-cm functional luminal imaging probe (FLIP) during endoscopy were evaluated in a cross-sectional study. FLIP panometry contractile response (CR) patterns were classified as normal CR or borderline CR if antegrade contractions were present, and abnormal CRs included impaired/disordered CR, absent CR, or spastic-reactive CR. The distensibility plateau of the esophageal body and esophagogastric junction distensibility was measured with FLIP.ResultsFLIP CR patterns included 68 (34%) normal CR, 65 (33%) borderline CR, 44 (22%) impaired/disordered CR, 16 (8%) absent CR, and 6 (3%) spastic-reactive CR. Compared with normal CRs, abnormal CRs more frequently had reduced esophageal distensibility (distensibility plateau <17 mm in 56% vs 32%), greater total EoE reference scores (median, 5; interquartile range [IQR], 3-6 vs median, 4; IQR, 3-5) with more severe ring scores, and a greater duration of symptoms (median, 10 y; IQR, 4-23 y vs median, 7 y; IQR, 3-15 y). Mucosal eosinophil density, however, was similar between abnormal CRs and normal CRs (median, 34 eosinophils/high-power field [hpf]; IQR, 14-60 eosinophils/hpf vs median, 25 eosinophils/hpf; IQR, 5-50 eosinophils/hpf).ConclusionsAlthough normal secondary peristalsis was observed frequently in this EoE cohort, abnormal esophageal CRs were related to EoE disease severity, especially features of fibrostenosis. This study evaluating secondary peristalsis in EoE suggests that esophageal wall remodeling, rather than eosinophilic inflammatory intensity, was associated with esophageal dysmotility in EoE.

Dataset Information

Genetic variations in the TLR3 locus are associated with eosinophilic esophagitis.

Publications

Genetic variations in the <i>TLR3</i> locus are associated with eosinophilic esophagitis.

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