Replication and meta-analyses nominate numerous eosinophilic esophagitis risk genes

Abstract

CpG) award. M.T.W. is supported by the NIH (grant no. R01 NS099068), a Cincinnati Children's Research Foundation Endowed Scholar Award, and a CCHMC CpG award. M.E.R.'s work is funded by the NIH (grant nos. R37 AI045898, U19 AI070235, R01 AI057803, R01 HG010730, and R01 AR073228); the Campaign Urging Research for Eosinophilic Disease; and the Sunshine Charitable Foundation and its supporters, Denise and David Bunning. This study was originally funded by the Consortium of Food Allergy Researchers (COFAR, National Institute of Allergy and Infectious Diseases grant no. U19AI066738). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Disclosure of potential conflict of interest: V. Mukkada is a consultant for Shire, a Takeda company. T. Wen is a coinventor of the EoE diagnostic panel, a patent owned by Cincinnati Children's Hospital Medical Center, and serves as a consultant for NanoString Technologies, Inc, and a consultant committee member for GlaxoSmithKline. M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celgene, Astra Zeneca, Arena Pharmaceuticals, Guidepoint, and Suvretta Capital Management; has an equity interest in the first 5 listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest.

Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

“…As a confirmation of the major role of this cytokine in EoE, the TSLP locus (5q22) is highly associated with EoE in multiple GWAS studies (Sherrill et al, 2010;Kottyan et al, 2014Kottyan et al, , 2021 21 Clinicaltrials.gov Available online at: https://clinicaltrials.gov/ct2/show/ NCT01808196 22 Clinicaltrials.gov Available online at: https://clinicaltrials.gov/ct2/show/ NCT03029091 Namjou et al, 2014;Sleiman et al, 2014). In particular, a TSLP single nucleotide polymorphism (SNP), that results in increased TSLP expression, correlates with EoE risk and increased basophil numbers (Rothenberg et al, 2010;Noti et al, 2013).…”

“…This protease is exclusively expressed in the esophageal mucosa (Sleiman et al, 2014;Kottyan et al, 2021) and is dynamically regulated by IL-13 (Kottyan et al, 2014). Higher levels of CAPN14 expression, such as seen in active EoE (Sleiman et al, 2014;Kottyan et al, 2021), are associated with the downregulation of DSG1, FLG, and zonulin, all involved in epithelial barrier function (Sleiman et al, 2014). Proteases also seem to play a role in EoE.…”

“…CAPN14 is an intracellular regulatory protease, member of the classical calpain subfamily, involved in the integrity of the esophageal epithelial barrier. This protease is exclusively expressed in the esophageal mucosa ( Sleiman et al, 2014 ; Kottyan et al, 2021 ) and is dynamically regulated by IL-13 ( Kottyan et al, 2014 ). Higher levels of CAPN14 expression, such as seen in active EoE ( Sleiman et al, 2014 ; Kottyan et al, 2021 ), are associated with the downregulation of DSG1, FLG, and zonulin, all involved in epithelial barrier function ( Sleiman et al, 2014 ).…”

“…Moreover, multiple genetic variants in epithelial barrier-related genes have been associated with an increased risk of developing EoE in life. These include two coding variants in FLG gene (R501X and 2282del4), associated with EoE irrespective of atopic status ( Blanchard et al, 2010 ), a genetic risk locus located on chr19q13.11 that encodes several genes (ANKRD27, PDCD5) involved in apical transport in esophageal epithelial cells, wound healing ( Tamura et al, 2011 ; Fukuda, 2016 ), transcriptional regulation, DNA damage response, and cell cycle control ( Li et al, 2016 ), a variant in the 10p14 locus in an intron of Inter-α-trypsin inhibitor heavy chain 5 (ITIH5), a gene that encodes for a serine protease inhibitor and has been also linked to eosinophilic granulomatosis with polyangiitis ( Kottyan et al, 2021 ), and a locus on chr2p23.1, involving the CAPN14 gene, was found to be highly associated with EoE in multiple studies ( Kottyan et al, 2014 , 2021 ; Sleiman et al, 2014 ).…”

Immune system and microbiome in the esophagus: implications for understanding inflammatory diseases

“…An impaired epithelial barrier has been described in EoE with reduced proteins required to maintain the intact esophageal epithelial barrier, such as filaggrin and desmoglein, combined with dilated intercellular spaces between epithelial cells [5,6,106]. Interestingly, genome-wide association studies suggested genetic risk variants of genes expressed by epithelial and immune cells in EoE [107]. The identified single nucleotide polymorphisms included TSLP [108]; c11orf30, STAT6, and ANKRD27 [109]; cytosolic calciumactivated cysteine proteases CAPN14 (calpain-14) [110]; and the filament aggregating protein filaggrin [111].…”