Trends in Molecular Medicine
ReviewA genetic perspective on coeliac disease
Section snippets
Coeliac disease
Coeliac disease is an inflammatory disorder with an autoimmune component. The prevalence of coeliac disease in populations of white European origin is estimated at 1–3% [1]. The classic manifestation of coeliac disease includes diarrhoea, abdominal distension, failure to thrive and short stature [2]. Many patients present with extraintestinal manifestations, such as dermatitis herpetiformis, anaemia, neurological symptoms or osteoporosis 3, 4. This wide spectrum means coeliac disease is
The risk of HLA
HLA class II molecules are the major risk factors predisposing individuals to coeliac disease and account for ∼35% of the genetic risk [19]. Over 90% of patients with coeliac disease express the HLA-DQ2 heterodimer and the remainder express HLA-DQ8 molecules. HLA-DQ2 is encoded by the HLA-DQA1*05 allele (α chain) and HLA-DQB1*02 allele (β chain). The two alleles are often present in the cis conformation on the DR3 haplotype, which is also common to many other autoimmune disorders [20]. The
Coeliac disease pathways
The 39 nonHLA coeliac loci together encompass 115 different genes (based on LD blocks [19]). At least 28 of the nonHLA coeliac loci harbour immune-related genes, pointing to an altered immune system response underlying coeliac disease. Based on our knowledge of coeliac disease biology, the most plausible immune-related genes from these 28 regions can be grouped into several immune-related pathways. Many of these genes have broad functions and regulate several pathways. Below we describe how
Individual risk profiling for coeliac disease
Similar to the majority of complex traits evaluated so far by GWAS, the nonHLA genes show a modest individual risk and all 39 loci together explain only ∼5% of the risk for coeliac disease [19]. Although 5% might seem to account for only a small proportion of the total genetic risk, it can be used to assess an individual's risk for coeliac disease. The first step in determining individual risk is to assess their HLA status because the absence of HLA-DQ2/DQ8 is a strong predictor of not
Genetic sharing of coeliac disease with other traits
Many coeliac disease risk loci are shared with other immune-related diseases 25, 49, 50, which supports observations that autoimmune diseases co-occur in families and individuals [51]. Coeliac disease often co-occurs with type 1 diabetes, rheumatoid arthritis, ulcerative colitis or Crohn's disease 51, 52, 53.
A shared genetic background among these diseases points to common biological pathways underlying their aetiology. To obtain an unbiased picture of the shared genetics, we used ‘A Catalogue
Pathway classification
We used our GWAS results to further our understanding of known pathways involved in coeliac disease by selecting relevant, immune-related genes from the different associated loci. As such an approach is highly biased, we also applied DAVID, a pathway analysis tool (Box 2). We acknowledge that these tools are especially biased towards detecting the well-defined pathways [55] when analysing a random selection of SNPs. Although this analysis can indicate the biological processes involved in the
Concluding remarks and future perspectives
At this time, 39 nonHLA genes are known to contribute to the susceptibility for coeliac disease. Although the findings account for a rather modest amount (∼5%) of the total genetic risk, these genetic studies have expanded our understanding of the biology of coeliac disease and broadened the repertoire of immune pathways driving disease development. Genetic findings have now not only confirmed the well-established role of the adaptive immune response but have also indicated a clear role for the
Acknowledgements
We thank Jihane Romanos, Cleo van Diemen, Alexandra Zhernakova and Jackie Senior for critically reading the manuscript. Our research is supported by grants from the Coeliac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to C.W.), the Netherlands Organisation for Scientific Research (NWO-VICI grant 918.66.620 to C.W.) and grants from the Wellcome Trust, Juvenile Diabetes Research Foundation
References (94)
Increased prevalence and mortality in undiagnosed celiac disease
Gastroenterology
(2009)Morbidity and mortality among older individuals with undiagnosed celiac disease
Gastroenterology
(2010)HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7
Hum. Immunol.
(1992)Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease
Gastroenterology
(1998)Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease
Immunity
(2004)Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3
Biochem. Biophys. Res. Commun.
(1997)Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection
Am. J. Hum. Genet.
(2010)The extracellular part of (zeta) is buried in the T cell antigen receptor complex
Immunol. Lett.
(2008)Gliadin as a stimulator of innate responses in celiac disease
Mol. Immunol.
(2005)Epidemiology of autoimmune diseases in Denmark
J. Autoimmun.
(2007)
Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk
Gastroenterology
Voxelwise genome-wide association study (vGWAS)
Neuroimage
Genome-wide association study of tanning phenotype in a population of European ancestry
J. Invest. Dermatol.
Prevalence of celiac disease among children in Finland
N. Engl. J. Med.
Presentation of pediatric celiac disease in the United States: prominent effect of breastfeeding
Clin. Pediatr.
Trends in the presentation of celiac disease
Am. J. Med.
The many faces of celiac disease: clinical presentation of celiac disease in the adult population
Gastroenterology
Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience
Gut
Mortality in celiac disease
Nat. Rev. Gastroenterol. Hepatol.
Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease
Nat. Med.
Tissue-mediated control of immunopathology in coeliac disease
Nat. Rev. Immunol.
Evidence for a primary association of celiac disease to a particular HLA-DQ (alpha)/(beta) heterodimer
J. Exp. Med.
The intestinal T cell response to (alpha)-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase
J. Exp. Med.
Celiac disease
N. Engl. J. Med.
Identification of tissue transglutaminase as the autoantigen of celiac disease
Nat. Med.
Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease
Sci. Transl. Med.
Multiple common variants for celiac disease influencing immune gene expression
Nat. Genet.
The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases
Immunol. Rev.
Concordance, disease progression, and heritability of coeliac disease in Italian twins
Gut
A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21
Nat. Genet.
Newly identified genetic risk variants for celiac disease related to the immune response
Nat. Genet.
Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-(kappa)B signalling
Gut
Shared and distinct genetic variants in type 1 diabetes and celiac disease
N. Engl. J. Med.
Replication of celiac disease UK genome-wide association study results in a US population
Hum. Mol. Genet.
Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes
Science
The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH -17 cells
Nat. Immunol.
Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS
Int. Immunol.
Induction and effector functions of TH17 cells
Nature
Regulation of gut inflammation and Th17 cell response by interleukin-21
Gastroenterology
Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity
Nat. Genet.
Antigen presentation in the thymus for positive selection and central tolerance induction
Nat. Rev. Immunol.
Themis imposes new law and order on positive selection
Nat. Immunol.
The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus
J. Exp. Med.
LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)-mediated thymocyte deletion is dependent on the interaction between TCR and MHC/self-peptide
J. Immunol.
IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors
Nat. Rev. Immunol.
Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading
Nat. Med.
Antiviral immune responses: triggers of or triggered by autoimmunity? Nat
Rev. Immunol.
Cited by (106)
Celiac disease
2023, Encyclopedia of Human Nutrition: Volume 1-4, Fourth EditionGluten Intake and Risk of Digestive System Cancers in 3 Large Prospective Cohort Studies
2022, Clinical Gastroenterology and HepatologyCitation Excerpt :Because of its high proline content, gluten cannot be completely digested by human proteases. In consequence, as illustrated by in vitro and in vivo studies,25,26 toxic proline-rich 33-mer peptides incite immune response and promote inflammation in individuals genetically susceptible to CD, which has been linked to an increased risk of certain digestive system cancers, including small intestinal cancer and esophageal cancer.8–10 In turn, a gluten-free diet can resolve symptoms and normalize intestinal mucosa in CD.27
The early gut microbiome and the risk of chronic disease
2021, The Human Microbiome in Early Life: Implications to Health and DiseaseAssociation Between Antibiotics in the First Year of Life and Celiac Disease
2019, GastroenterologyImmunoreactive cereal proteins in wheat allergy, non-celiac gluten/wheat sensitivity (NCGS) and celiac disease
2019, Current Opinion in Food ScienceCitation Excerpt :While there is a mounting body of evidence to support an increasing prevalence of wheat hypersensitivities [35,36] (and allergies and autoimmune diseases in general [37]) in the population, the underlying causative factors have not been identified so far. The most likely factors on the side of the human immune system include the low frequency of infections due to improved hygiene [20], antibiotics and vaccinations, changed intestinal permeability [38], decreased exposure to airborne bacteria and changed dietary habits such as ingestion of more ω-6 and less ω-3 fatty acids and less antioxidants that in turn affect gut microbiota [39,40]. On the side of cereals, changes in protein composition may have resulted in higher contents of immunoreactive components due to different protein expression patterns in diploid, tetraploid and hexaploid wheat species [41,42], breeding [43–47], heat and cold stress [49••] and agricultural practices including fertilization.