Sallese Michele, Lopetuso Loris Riccardo, Efthymakis Konstantinos, Neri Matteo
Department of Medical, Oral and Biotechnological Sciences, 'G. D'Annunzio' University of Chieti-Pescara, Chieti, Italy.
Center for Advanced Studies and Technology (CAST), 'G. D'Annunzio' University of Chieti-Pescara, Chieti, Italy.
Front Nutr. 2020 Nov 12;7:575844. doi: 10.3389/fnut.2020.575844. eCollection 2020.
Most common food grains contain gluten proteins and can cause adverse medical conditions generally known as gluten-related disorders. Celiac disease is an immune-mediated enteropathy triggered by gluten in individuals carrying a specific genetic make-up. The presence of the human leukocyte antigens (HLA)-DQ2 and HLA-DQ8 haplotypes together with gluten intake is a necessary, although not sufficient, condition, to develop celiac disease. Fine mapping of the human genome has revealed numerous genetic variants important in the development of this disease. Most of the genetic variants are small nucleotide polymorphisms located within promoters and transcriptional enhancer sequences. Their importance is underlined by an increased risk in DQ2/DQ8 carriers who also have these non-HLA alleles. In addition, several immune-mediated diseases share susceptibility loci with celiac disease, shedding light on the reasons for co-occurrence between these diseases. Finally, most of the genes potentially involved in celiac disease by fine genetic mapping of non-HLA loci were confirmed in gene expression studies. In contrast to celiac disease, very little is known about the genetic make-up of non-celiac wheat sensitivity (NCWS), a clinically defined pathology that shares symptoms and gluten dependence with the celiac disease. We recently identified differentially expressed genes and miRNAs in the intestinal mucosa of these patients. Remarkably, the differentially expressed genes were long non-coding RNAs possibly involved in the regulation of cell functions. Thus, we can speculate that important aspects of these diseases depend on alteration of regulatory genetic circuits. Furthermore, our finding suggests that innate immune response is involved in the pathogenic mechanism of NCWS. This review is intended to convey the idea that in order to fully understand celiac disease and its relationship with other gluten-related disorders, it is worth learning more about non-HLA variants.
大多数常见的谷物含有麸质蛋白，可能会引发一般被称为麸质相关疾病的不良医学状况。乳糜泻是一种由麸质引发的免疫介导性肠病，发生在具有特定基因构成的个体中。人类白细胞抗原（HLA）-DQ2和HLA-DQ8单倍型的存在以及麸质的摄入是患乳糜泻的必要条件，尽管并不充分。人类基因组的精细定位揭示了许多在该疾病发展中起重要作用的基因变异。大多数基因变异是位于启动子和转录增强子序列内的小核苷酸多态性。在同时携带这些非HLA等位基因的DQ2/DQ8携带者中风险增加，凸显了它们的重要性。此外，几种免疫介导性疾病与乳糜泻共享易感基因座，这为这些疾病同时发生的原因提供了线索。最后，通过非HLA基因座的精细基因定位，大多数可能与乳糜泻相关的基因在基因表达研究中得到了证实。与乳糜泻形成对比的是，对于非乳糜泻性小麦敏感（NCWS）的基因构成知之甚少，NCWS是一种临床定义的病理状况，与乳糜泻有共同的症状且依赖麸质。我们最近在这些患者的肠黏膜中鉴定出了差异表达的基因和微小RNA。值得注意的是，差异表达的基因是可能参与细胞功能调节的长链非编码RNA。因此，我们可以推测这些疾病的重要方面取决于调控基因回路的改变。此外，我们的发现表明先天免疫反应参与了NCWS的致病机制。这篇综述旨在传达这样一个观点，即要全面理解乳糜泻及其与其他麸质相关疾病的关系，有必要更多地了解非HLA变异。
