Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome

IF 6.3 2区 医学 Q1 ALLERGY Clinical and Experimental Allergy Pub Date : 2024-09-30 DOI:10.1111/cea.14564
Alba Camino-Mera, Jacobo Pardo-Seco, Xabier Bello, Laura Argiz, Robert J. Boyle, Adnan Custovic, Jethro Herberg, Myrsini Kaforou, Stefania Arasi, Alessandro Fiocchi, Valentina Pecora, Simona Barni, Francesca Mori, Teresa Bracamonte, Luis Echeverria, Virginia O'Valle-Aísa, Noelia Lara Hernández-Martínez, Iria Carballeira, Emilio García, Carlos Garcia-Magan, José Domingo Moure-González, Purificación Gonzalez-Delgado, Teresa Garriga-Baraut, Sonsoles Infante, Gabriela Zambrano-Ibarra, Margarita Tomás-Pérez, Adrianna Machinena, Mariona Pascal, Ana Prieto, Sonia Vázquez-Cortes, Montserrat Fernández-Rivas, Leticia Vila, Laia Alsina, María José Torres, Giusi Mangone, Santiago Quirce, Federico Martinón-Torres, Marta Vázquez-Ortiz, Alberto Gómez-Carballa, Antonio Salas
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Abstract

Background

Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology—key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES.

Methods

Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study.

Results

Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon).

Conclusions

This study represents the first case–control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients.

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全外显子组测序发现食物蛋白诱发小肠结肠炎综合征的上皮和免疫功能障碍相关生物标记物
背景:食物蛋白诱发小肠结肠炎综合征(FPIES)是一种主要影响婴儿的食物过敏症,通常会导致呕吐和休克。由于对其病理生理学知之甚少且缺乏特异性生物标志物,诊断常常被延误。了解FPIES的遗传学可以揭示疾病的易感性和病理生理学--这是制定诊断、预后、预防和治疗策略的关键。我们利用一组特征明确的患者,探讨了FPIES潜在的全基因组易感因素:方法:我们收集了 41 名经口腔食物挑战证实的 FPIES 患者的血液样本,进行了一项全面的全外显子组测序关联研究:结果:包括rs872786 (RBM8A)、rs2241880 (ATG16L1)和rs2289477 (ATG16L1)在内的显著遗传变异被确定为FPIES的重要发现。加权 SKAT 模型确定了其他六个相关基因,包括 DGKZ 和 SIRPA。DGKZ 可诱导 TGF-β 信号,对上皮屏障的完整性和 IgA 的产生至关重要;RBM8A 与血小板减少缺失半径综合征有关,经常与牛奶过敏有关;SIRPA 与炎症组织中的中性粒细胞/单核细胞增多有关,经常在 FPIES 中观察到;ATG16L1 与炎症性肠病有关。共表达相关性分析表明,RBM8A 与胃肠组织中的丝状绒毛蛋白基因(FLG)存在功能相关性,而丝状绒毛蛋白是已知的 IgE 介导的食物过敏的关键致病因素和风险因素。一项全转录组关联研究表明,患者的遗传变异会影响 RBM8A(胃和胰腺)和 ATG16L1(横结肠)的基因表达:这项研究是对 FPIES 患者进行的首次病例对照外显子组关联研究,标志着向揭示该综合征的遗传易感因素迈出了关键一步。我们的研究结果强调了导致 FPIES 的潜在因素和途径,包括上皮屏障功能障碍和免疫失调。虽然这些结果很新颖,但还只是初步的,需要在第二批患者中进一步验证。
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来源期刊
CiteScore
10.40
自引率
9.80%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Allergy strikes an excellent balance between clinical and scientific articles and carries regular reviews and editorials written by leading authorities in their field. In response to the increasing number of quality submissions, since 1996 the journals size has increased by over 30%. Clinical & Experimental Allergy is essential reading for allergy practitioners and research scientists with an interest in allergic diseases and mechanisms. Truly international in appeal, Clinical & Experimental Allergy publishes clinical and experimental observations in disease in all fields of medicine in which allergic hypersensitivity plays a part.
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