Replication and meta-analyses nominate numerous eosinophilic esophagitis risk genes - 09/01/21
Abstract |
Background |
Eosinophilic esophagitis (EoE) is an emerging, chronic, rare allergic disease associated with marked eosinophil accumulation in the esophagus. Previous genome-wide association studies have provided strong evidence for 3 genome-wide susceptibility loci.
Objective |
We sought to replicate known and suggestive EoE genetic risk loci and conduct a meta-analysis of previously reported data sets.
Methods |
An EoE-Custom single-nucleotide polymophism (SNP) Chip containing 956 candidate EoE risk single-nucleotide polymorphisms was used to genotype 627 cases and 365 controls. Statistical power was enhanced by adding 1959 external controls and performing meta-analyses with 2 independent EoE genome-wide association studies.
Results |
Meta-analysis identified replicated association and genome-wide significance at 6 loci: 2p23 (2 independent genetic effects) and 5q22, 10p14, 11q13, and 16p13. Seven additional loci were identified at suggestive significance (P < 10−6): 1q31, 5q23, 6q15, 6q21, 8p21, 17q12, and 22q13. From these risk loci, 13 protein-coding EoE candidate risk genes were expressed in a genotype-dependent manner. EoE risk genes were expressed in disease-relevant cell types, including esophageal epithelia, fibroblasts, and immune cells, with some expressed as a function of disease activity. The genetic risk burden of EoE-associated genetic variants was markedly larger in cases relative to controls (P < 10−38); individuals with the highest decile of genetic burden had greater than 12-fold risk of EoE compared with those within the lowest decile.
Conclusions |
This study extends the genetic underpinnings of EoE, highlighting 13 genes whose genotype-dependent expression expands our etiologic understanding of EoE and provides a framework for a polygenic risk score to be validated in future studies.
Il testo completo di questo articolo è disponibile in PDF.Graphical abstract |
Key words : Allergy, genetics, esophagitis, eosinophil, epithelium, polymorphism, variant, atopy
Abbreviations used : CCHMC, EoE, EoE-CSC, eQTL, GTEx, GWAS, SNP
Mappa
| L.C.K. is funded by the National Institutes of Health (NIH) (grant nos. R01 DK107502, R01 AR073228, and P30 AR070549) and a Cincinnati Children's Hospital Medical Center (CCHMC) Center for Pediatrics Genomics (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. |
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| 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. |
Vol 147 - N° 1
P. 255-266 - Gennaio 2021 Ritorno al numero
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