A Possible Mechanism behind Autoimmune Disorders Discovered By Genome-Wide Linkage and Association Analysis in Celiac Disease

Abstract

Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS) have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1) polarity and epithelial cell functionality; 2) intestinal smooth muscle; 3) growth and energy homeostasis, including proline and glutamine metabolism; and finally 4) innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly also other chronic disorders with an inflammatory component.

The genetics of celiac disease: A comprehensive review of clinical implications

“…They identified a new genome-wide significant risk locus covering the DUSP10 gene after stratifying for HLA-DQ risk factors [49].…”

“…It must be considered that variants in REL and TNFAIP3 genes were associated to CD risk [42] and that NFkB was suggested to be a mediator of the changes induced by gliadin leading to the increase of IL-15 and augmented intestinal permeability, which have been consistently linked to CD pathogenesis. € Ostensson et al [49] performed two-locus interaction analysis and pathways analysis and established several functional categories involved in CD: polarity and epithelial cell functionality, intestinal smooth muscle, growth and energy homeostasis; and innate and adaptive immune system. Based on these, the authors propose a pathogenic model involving a slight dysfunction combining those categories and gluten consumption, which would lead to a metabolic imbalance that, in absence of a pathogen, could trigger an immunological response against "self-antigens" (TG2) and tissue destruction.…”

Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study

“…Therefore, further biological and epidemiological studies are warranted. Regarding the locus found to be associated with the risk of CKD on chr 4 (4q23), microsomal triglyceride transfer protein ( MTTP ) gene encoded by this locus is reportedly associated with the risk of celiac disease in Caucasians, although the roles of genomic locus in the genesis of human CKD remain largely unknown [34]. MTTP reportedly catalyzes the transport of lipids between phospholipid surfaces, and its genetic variation is associated with abetalipoproteinemia and glucose tolerance [35].…”

Dietary gluten and the development of celiac disease and type 1 diabetes

“…48 Also, a recent genome-wide linkage and association analysis has shown the presence in CD of two out of three loci already known to be involved in regulating plasma glucose levels in T1DM. 49 CD and T1DM also share the IL-2/21 susceptibility locus, which is known to be associated with multiple autoimmune diseases. [50][51][52] In particular, all these studies highlight the role of IL-21, which is known to induce interferon-γ production and regulate proliferation and survival of natural killer and CD8 T-cells in several autoimmune diseases.…”