Beyond the HLA Genes in Gluten-Related Disorders

Abstract

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.

Review article: Epidemiology of coeliac disease

“…IL-2 is involved in T-cell activation and proliferation while IL-21 enhances B-cell, T-cell and NK-cell proliferation. 115 Interestingly, the presence of both HLA and non-HLA alleles has been found to favour the occurrence of CD. The risk of developing CD increased sixfold in the presence of 13 non-HLA alleles along with typical HLA genes, compared to those with zero to five alleles.…”

“…While HLA molecules play very significant role in the pathogenesis of CD, only HLA related factors are not sufficient to explain the occurrence of the disease in ~3% of all individuals harbouring HLA-DQ2 or DQ8 haplotype. 115 Sequencing of the human genome opened the possibility of mapping genetic variants and analysing their association with complex diseases. Many additional genetic loci, outside the HLA region, have been found to be associated with CD, [116][117][118] the relative risk of each of these other non-HLA genes is small.…”

Gluten-related disorders

“…[1,23]. HLA DQ2 haplotype is identified in about 90% and HLA DQ8 haplotype in about 10% of patients with CD [23][24][25]. However, the disease expression, besides genetic predisposition and exposure to gluten, also requires the influence of other external factors [1,23,26].…”

Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment

“…The majority of patients with CeD, up to 90%, carry DQ2, and the reminder DQ8 (Figure 1). HLA-DQ2.5 is encoded by the DQA 62 On average, 35% of most populations are carriers of DQ2 and/or DQ8, and roughly 1% will develop CeD. Therefore, on the population level this carrier state entails a 3-fold increased risk for CeD.…”

“…Moreover, the presence of 2 versus 1 DQ2.5 gene, ie, homoversus heterozygosity, incurs an estimated up to 5-fold increased risk to develop CeD compared with heterozygotes. 49,62,63 The structural basis of gluten peptide binding has been defined by molecular and X-ray structural analysis of the complex between a (deamidated) alpha-gliadin and a glutenin peptide with DQ2.5 and DQ2.2, respectively. For DQ2.2 versus DQ2.5, the 9-amino-acid antigen-binding pocket requires a serine at position 3 other than DQ2.5.…”