Review
A genetic perspective on coeliac disease

https://doi.org/10.1016/j.molmed.2010.09.003Get rights and content

Coeliac disease is an inflammatory disorder of the small intestine with an autoimmune component and strong heritability. Genetic studies have confirmed strong association to HLA and identified 39 nonHLA risk genes, mostly immune-related. Over 50% of the disease-associated single nucleotide polymorphisms are correlated with gene expression. Most of the coeliac disease-associated regions are shared with other immune-related diseases, as well as with metabolic, haematological or neurological traits, or cancer. We review recent progress in the genetics of coeliac disease and describe the pathways these genes are in, the functional consequences of the associated markers on gene expression and the genes shared between coeliac disease and other traits.

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)

  • R. Cui

    Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk

    Gastroenterology

    (2009)
  • J.L. Stein

    Voxelwise genome-wide association study (vGWAS)

    Neuroimage

    (2010)
  • H. Nan

    Genome-wide association study of tanning phenotype in a population of European ancestry

    J. Invest. Dermatol.

    (2009)
  • M. Maki

    Prevalence of celiac disease among children in Finland

    N. Engl. J. Med.

    (2003)
  • M.A. D’Amico

    Presentation of pediatric celiac disease in the United States: prominent effect of breastfeeding

    Clin. Pediatr.

    (2005)
  • S.D. Rampertab

    Trends in the presentation of celiac disease

    Am. J. Med.

    (2006)
  • P.H. Green

    The many faces of celiac disease: clinical presentation of celiac disease in the adult population

    Gastroenterology

    (2005)
  • A. Al-toma

    Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience

    Gut

    (2007)
  • F. Biagi et al.

    Mortality in celiac disease

    Nat. Rev. Gastroenterol. Hepatol.

    (2010)
  • O. Molberg

    Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease

    Nat. Med.

    (1998)
  • B. Jabri et al.

    Tissue-mediated control of immunopathology in coeliac disease

    Nat. Rev. Immunol.

    (2009)
  • L.M. Sollid

    Evidence for a primary association of celiac disease to a particular HLA-DQ (alpha)/(beta) heterodimer

    J. Exp. Med.

    (1989)
  • H. Arentz-Hansen

    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.

    (2000)
  • P.H. Green et al.

    Celiac disease

    N. Engl. J. Med.

    (2007)
  • W. Dieterich

    Identification of tissue transglutaminase as the autoantigen of celiac disease

    Nat. Med.

    (1997)
  • J.A. Tye-Din

    Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease

    Sci. Transl. Med.

    (2010)
  • P.C.A. Dubois

    Multiple common variants for celiac disease influencing immune gene expression

    Nat. Genet.

    (2010)
  • P. Price

    The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases

    Immunol. Rev.

    (1999)
  • L. Nistico

    Concordance, disease progression, and heritability of coeliac disease in Italian twins

    Gut

    (2006)
  • D.A. Van Heel

    A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

    Nat. Genet.

    (2007)
  • K.A. Hunt

    Newly identified genetic risk variants for celiac disease related to the immune response

    Nat. Genet.

    (2008)
  • G. Trynka

    Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-(kappa)B signalling

    Gut

    (2009)
  • D.J. Smyth

    Shared and distinct genetic variants in type 1 diabetes and celiac disease

    N. Engl. J. Med.

    (2008)
  • C.P. Garner

    Replication of celiac disease UK genome-wide association study results in a US population

    Hum. Mol. Genet.

    (2009)
  • S. Nejentsev

    Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes

    Science

    (2009)
  • A.T. Bauquet

    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.

    (2009)
  • S.K. Yoshinaga

    Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS

    Int. Immunol.

    (2000)
  • E. Bettelli

    Induction and effector functions of TH17 cells

    Nature

    (2008)
  • D. Fina

    Regulation of gut inflammation and Th17 cell response by interleukin-21

    Gastroenterology

    (2008)
  • J. Yamanouchi

    Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity

    Nat. Genet.

    (2007)
  • L. Klein

    Antigen presentation in the thymus for positive selection and central tolerance induction

    Nat. Rev. Immunol.

    (2009)
  • P.M. Allen

    Themis imposes new law and order on positive selection

    Nat. Immunol.

    (2009)
  • M. Zamisch

    The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus

    J. Exp. Med.

    (2009)
  • J. Wang et al.

    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.

    (2003)
  • K. Honda et al.

    IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors

    Nat. Rev. Immunol.

    (2006)
  • S.D. Miller

    Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading

    Nat. Med.

    (1997)
  • C. Munz

    Antiviral immune responses: triggers of or triggered by autoimmunity? Nat

    Rev. Immunol.

    (2009)
  • Cited by (106)

    • Celiac disease

      2023, Encyclopedia of Human Nutrition: Volume 1-4, Fourth Edition
    • Gluten Intake and Risk of Digestive System Cancers in 3 Large Prospective Cohort Studies

      2022, Clinical Gastroenterology and Hepatology
      Citation 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 Disease
    • Immunoreactive cereal proteins in wheat allergy, non-celiac gluten/wheat sensitivity (NCGS) and celiac disease

      2019, Current Opinion in Food Science
      Citation 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.

    View all citing articles on Scopus
    View full text