Searching for genes influencing a complex disease: the case of coeliac disease

Abstract

Recently, a few genes have been reported to be causative in inflammatory diseases. Still, we are waiting for the vast majority to be discovered. New tools for genotyping and statistical analysis have been developed and emphasis has been put on study design. Coeliac disease (CD) is a disorder, where prolamins in dietary wheat gluten and related proteins from rye or barley are not tolerated. It is one of the most common chronic diseases in humans exceeding a population prevalence of 1%. In this article, we will summarise what is currently known about the genetics influencing CD with the emphasis on the non-HLA genetic component. We will discuss some difficulties when searching for susceptibility genes in disorders with complex inheritance patterns.

The cytokine interleukin 21: a new player in coeliac disease?

“…The strongest association with CD was found approximately 24 kb 5′ of the IL21 gene and was highly significant, with a p value of 1.3×10 −14 and an odds ratio of 0.63. This study extends the already large list of potential candidate chromosomal regions associated with CD (for a review, see Naluai et al 4) and supports the hypothesis that CD is, as is the case for type I diabetes (TID), a classical model of polygenic disease with a small number of genes with large effects, mainly MHC class II genes, and a large number of genes with small effects 5. Moreover, this study suggests for the first time in CD the potential role of IL2, a cytokine important for the homeostasis and function of regulatory T cells, and of IL21, a more recently identified cytokine that is structurally related to IL2 but possesses distinct immune functions 6 – 8.…”

Celiac disease and HLA-DQ genotype: diagnosis of different genetic risk profiles related to the age in Badajoz, southwestern Spain

“…It is well known that environmental factors and non-HLA alleles are involved in CD development (7,(12)(13)(14)(15)(16)(17). Over the past three decades in western countries, the prevalence of CD, as well as other autoimmune diseases, has had a huge increase; in CD, the use of more sensitive and specific markers, and the better understanding of the clinical forms of the disease, have increased the number of diagnosed patients.…”

“…Indeed, more than 90 % of celiac patients carry the molecule DQ2, encoded by DQA1*05/DQB1*02, whereas most of the remaining patients carry DQ8, encoded by DQA1*03/DQB1*0302 (7). These molecules are almost necessary, but not sufficient for disease development, being present in more than 30% of Caucasian individuals (8)(9)(10)(11); thus, non-HLA loci must also contribute to the development of CD (7,(12)(13)(14)(15)(16)(17). There is compelling evidence that CD4 T cell response to HLA-DQ (2 or 8)-bound gluten-derived peptides (modified by tissue transglutaminase) are the primary pathogenic mechanism to disease (18).…”

Artificial Intelligence Analysis of Celiac Disease Using an Autoimmune Discovery Transcriptomic Panel Highlighted Pathogenic Genes including BTLA

“…This immune disorder occurs in genetically predisposed patients after induction by an environmental factor, which is gluten in the diet, found in cereals. More than 99% of the patients have HLA DR3-DQ2 and/or the DR4-DQ8 [ 2 , 3 , 4 ], but other non-HLA locus genes may also be involved in the disease pathogenesis, such as TNFAIP3 (A20) , REL , NKG2D , MICA , CTLA4 , MMP3 , MIF , and etcetera [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Celiac disease is associated with several autoimmune disorders, such as type 1 diabetes mellitus and autoimmune thyroid disease [ 16 , 17 ].…”