Celiac Disease: From Pathogenesis to Novel Therapies
2009; Elsevier BV; Volume: 137; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2009.09.008
ISSN1528-0012
AutoresDetlef Schuppan, Yvonne Junker, Donatella Barisani,
Tópico(s)Microscopic Colitis
ResumoCeliac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by (1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4+ T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically. Celiac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by (1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4+ T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically. Celiac disease is a common inflammatory disease of the small intestine that is mainly triggered and maintained by the storage proteins (gluten) of wheat, barley, and rye in genetically predisposed individuals. Patients display various degrees of intestinal inflammation, ranging from mere intraepithelial lymphocytosis to severe subepithelial (lamina propria) mononuclear cell infiltration resulting in total villous atrophy coupled with crypt hyperplasia. Accordingly, clinical symptoms and laboratory indices range from completely asymptomatic to global malabsorption.1Abdulkarim A.S. Murray J.A. Celiac disease.Curr Treat Options Gastroenterol. 2002; 5: 27-38Google Scholar, 2Ciclitira P.J. King A.L. Fraser J.S. AGA technical review on Celiac Sprue American Gastroenterological Association.Gastroenterology. 2001; 120: 1526-1540Google Scholar, 3Farrell R.J. Kelly C.P. Celiac sprue.N Engl J Med. 2002; 346: 180-188Google Scholar, 4Green P.H. Cellier C. Celiac disease.N Engl J Med. 2007; 357: 1731-1743Google Scholar, 5Green P.H. Jabri B. Coeliac disease.Lancet. 2003; 362: 383-391Abstract Full Text Full Text PDF Scopus (770) Google Scholar, 6Schuppan D. 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Luostarinen L. et al.Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study.BMC Gastroenterol. 2009; 9: 49Google Scholar The majority (>80%) of patients with screening-detected celiac disease show no, minor, or non–diarrhea-associated clinical symptoms (clinically silent, oligosymptomatic, or atypical celiac disease, respectively). Oligosymptomatic celiac disease is associated with anemia, osteoporosis, and an often compromised well-being and quality of life,13Green P.H. The many faces of celiac disease: clinical presentation of celiac disease in the adult population.Gastroenterology. 2005; 128: S74-S78Google Scholar which overlaps with atypical celiac disease that is characterized by extraintestinal symptoms such as arthritis, infertility, hypertransaminasemia, and even liver failure.1Abdulkarim A.S. Murray J.A. Celiac disease.Curr Treat Options Gastroenterol. 2002; 5: 27-38Google Scholar, 2Ciclitira P.J. King A.L. Fraser J.S. AGA technical review on Celiac Sprue American Gastroenterological Association.Gastroenterology. 2001; 120: 1526-1540Google Scholar, 3Farrell R.J. Kelly C.P. Celiac sprue.N Engl J Med. 2002; 346: 180-188Google Scholar, 4Green P.H. Cellier C. Celiac disease.N Engl J Med. 2007; 357: 1731-1743Google Scholar, 5Green P.H. Jabri B. Coeliac disease.Lancet. 2003; 362: 383-391Abstract Full Text Full Text PDF Scopus (770) Google Scholar, 10Fasano A. Berti I. Gerarduzzi T. et al.Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.Arch Intern Med. 2003; 163: 286-292Google Scholar, 11Maki M. Mustalahti K. Kokkonen J. et al.Prevalence of celiac disease among children in Finland.N Engl J Med. 2003; 348: 2517-2524Google Scholar Furthermore, gluten sensitivity without intestinal lesions but circulating celiac autoantibodies or mere antibodies to gliadin, which lack specificity for classic celiac disease,14Uibo O. Uibo R. Kleimola V. et al.Serum IgA anti-gliadin antibodies in an adult population sample High prevalence without celiac disease.Dig Dis Sci. 1993; 38: 2034-2037Google Scholar has been linked to otherwise unexplained neurologic or psychiatric disorders such as cerebellar ataxia, peripheral neuropathy, schizophrenia, or autism.15Cascella N.G. Kryszak D. Bhatti B. et al.Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population.Schizophr Bull. 2009 Jun 3; ([Epub ahead of print])Google Scholar, 16Catassi C. Ratsch I.M. Fabiani E. et al.Coeliac disease in the year 2000: exploring the iceberg.Lancet. 1994; 343: 200-203Abstract Google Scholar, 17Fasano A. Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum.Gastroenterology. 2001; 120: 636-651Google Scholar, 18Genuis S.J. Bouchard T.P. Celiac disease presenting as autism.J Child Neurol. 2009 Jun 29; ([Epub ahead of print])Google Scholar Because symptoms in patients may improve on a gluten-free diet, this has led to the suggestion of nutritional gluten sensitivity that does not manifest itself as the classic intestinal lesion but rather as extraintestinal (eg, neurologic disease).19Ford R.P. The gluten syndrome: a neurological disease.Med Hypotheses. 2009; 73: 438-440Google Scholar, 20Grossman G. Neurological complications of coeliac disease: what is the evidence?.Pract Neurol. 2008; 8: 77-89Google Scholar, 21Verdu E.F. Armstrong D. Murray J.A. Between celiac disease and irritable bowel syndrome: the “no man's land” of gluten sensitivity.Am J Gastroenterol. 2009; 104: 1587-1594Google Scholar Its relation to celiac disease is discussed controversially. Classic celiac disease is frequently found in conjunction with (other) autoimmune diseases, such as type 1 diabetes mellitus, autoimmune thyroiditis, autoimmune hepatitis, dermatitis herpetiformis, and autoimmune alopecia.22Ventura A. Magazzu G. Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease SIGEP Study Group for Autoimmune Disorders in Celiac Disease.Gastroenterology. 1999; 117: 297-303Abstract Full Text Full Text PDF Scopus (804) Google Scholar In addition, patients with long-standing undetected and untreated symptomatic celiac disease are at an increased risk for developing enteropathy-associated T-cell lymphoma, small bowel adenocarcinoma, and other cancers of the gastrointestinal tract.23Smedby K.E. Akerman M. Hildebrand H. et al.Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma.Gut. 2005; 54: 54-59Google Scholar, 24Viljamaa M. Kaukinen K. 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The only currently available treatment of celiac disease is a lifelong strict gluten-free diet, which is difficult to maintain and can lead to social isolation because modern diets are heavily based on products that contain gluten. Virtually all patients with celiac disease share the heterodimeric HLA class II genes HLA-DQ2 or HLA-DQ8 as common genetic background. These class II molecules are expressed on antigen-presenting cells, mainly macrophages, dendritic cells, and B cells. Gluten peptides are presented by these celiac disease–associated HLA class II molecules. This can lead to activation of gluten-specific CD4+ T-helper 1 (Th1) cells in the lamina propria that are central effector cells of the intestinal inflammation resulting in crypt hyperplasia and villus atrophy.6Schuppan D. Current concepts of celiac disease pathogenesis.Gastroenterology. 2000; 119: 234-242Abstract Full Text Full Text PDF Scopus (478) Google Scholar, 27Sollid L.M. Coeliac disease: dissecting a complex inflammatory disorder.Nat Rev Immunol. 2002; 2: 647-655Google Scholar However, HLA-DQ2 or HLA-DQ8 are expressed in 30%–35% of the populations where celiac disease is prevalent, with only ∼2%–5% of gene carriers developing celiac disease. This implicates other genetic as well as environmental factors as contributors to the manifestation of celiac disease.28Wolters V.M. Wijmenga C. Genetic background of celiac disease and its clinical implications.Am J Gastroenterol. 2008; 103: 190-195Google Scholar, 29Macdonald T.T. Monteleone G. Immunity, inflammation, and allergy in the gut.Science. 2005; 307: 1920-1925Google Scholar Recent genetic studies in large numbers of patients with celiac disease, relatives, and matched controls revealed additional risk factors, most of which are related to T-cell regulation and inflammation.30Dubois P.C. van Heel D.A. Translational mini-review series on the immunogenetics of gut disease: immunogenetics of coeliac disease.Clin Exp Immunol. 2008; 153: 162-173Google Scholar, 31Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar, 32Romanos J. van Diemen C.C. Nolte I.M. et al.Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease.Gastroenterology. 2009; 137: 834-840Google Scholar, 33van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 35Adamovic S. Amundsen S.S. Lie B.A. et al.Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families.Genes Immun. 2008; 9: 364-367Google Scholar, 36Babron M.C. Nilsson S. 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Samuelsson L. et al.The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders.Tissue Antigens. 2000; 56: 350-355Google Scholar, 47Romanos J. Barisani D. Trynka G. et al.Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease.J Med Genet. 2009; 46: 60-63Google Scholar, 48van Belzen M.J. Mulder C.J. Zhernakova A. et al.CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients.Eur J Hum Genet. 2004; 12: 782-785Google Scholar, 49Woolley N. Holopainen P. Ollikainen V. et al.A new locus for coeliac disease mapped to chromosome 15 in a population isolate.Hum Genet. 2002; 111: 40-45Google Scholar However, the overall genetic contribution of these polymorphisms combined was estimated at only 3%–4% as compared with 30%–35% for HLA-DQ2 or HLA-DQ8.33van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 34Petronzelli F. Bonamico M. Ferrante P. et al.Genetic contribution of the HLA region to the familial clustering of coeliac disease.Ann Hum Genet. 1997; 61: 307-317Google Scholar The 13 susceptibility loci that have been identified to date are summarized in Table 1.31Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar, 33van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 35Adamovic S. Amundsen S.S. Lie B.A. et al.Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families.Genes Immun. 2008; 9: 364-367Google Scholar, 36Babron M.C. Nilsson S. Adamovic S. et al.Meta and pooled analysis of European coeliac disease data.Eur J Hum Genet. 2003; 11: 828-834Google Scholar, 37Dema B. Martinez A. Fernandez-Arquero M. et al.Association of IL18RAP and CCR3 with celiac disease in the Spanish population.J Med Genet. 2009; 46: 617-619Google Scholar, 38Djilali-Saiah I. Schmitz J. Harfouch-Hammoud E. et al.CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.Gut. 1998; 43: 187-189Google Scholar, 39Garner C.P. Murray J.A. Ding Y.C. et al.Replication of celiac disease UK genome-wide association study results in a US population.Hum Mol Genet. 2009; 18: 4219-4225Google Scholar, 40Greco L. Corazza G. Babron M.C. et al.Genome search in celiac disease.Am J Hum Genet. 1998; 62: 669-675Google Scholar, 41Haimila K. Einarsdottir E. de Kauwe A. et al.The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.Genes Immun. 2009; 10: 151-161Google Scholar, 42Koskinen L.L. Einarsdottir E. Dukes E. et al.Association study of the IL18RAP locus in three European populations with coeliac disease.Hum Mol Genet. 2009; 18: 1148-1155Google Scholar, 43Liu J. Juo S.H. Holopainen P. et al.Genomewide linkage analysis of celiac disease in Finnish families.Am J Hum Genet. 2002; 70: 51-59Google Scholar, 44Monsuur A.J. de Bakker P.I. Alizadeh B.Z. et al.Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect.Nat Genet. 2005; 37: 1341-1344Google Scholar, 45Naluai A.T. Nilsson S. Gudjonsdottir A.H. et al.Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11.Eur J Hum Genet. 2001; 9: 938-944Google Scholar, 46Naluai A.T. Nilsson S. Samuelsson L. et al.The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders.Tissue Antigens. 2000; 56: 350-355Google Scholar, 47Romanos J. Barisani D. Trynka G. et al.Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease.J Med Genet. 2009; 46: 60-63Google Scholar, 48van Belzen M.J. Mulder C.J. Zhernakova A. et al.CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients.Eur J Hum Genet. 2004; 12: 782-785Google Scholar, 49Woolley N. Holopainen P. Ollikainen V. et al.A new locus for coeliac disease mapped to chromosome 15 in a population isolate.Hum Genet. 2002; 111: 40-45Google Scholar Furthermore, early exposure of infants to dietary gluten,50Norris J.M. Barriga K. Hoffenberg E.J. et al.Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.JAMA. 2005; 293: 2343-2351Google Scholar early infection with enteropathic viruses, or a change of the bacterial flora51Collado M.C. Calabuig M. Sanz Y. Differences between the fecal microbiota of coeliac infants and healthy controls.Curr Issues Intest Microbiol. 2007; 8: 9-14Google Scholar, 52Collado M.C. Donat E. Ribes-Koninckx C. et al.Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease.BMC Microbiol. 2008; 8: 232Google Scholar, 53Collado M.C. Donat E. Ribes-Koninckx C. et al.Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.J Clin Pathol. 2009; 62: 264-269Google Scholar, 54Pavone P. Nicolini E. Taibi R. et al.Rotavirus and celiac disease.Am J Gastroenterol. 2007; 102: 1831Google Scholar, 55Stene L.C. Honeyman M.C. Hoffenberg E.J. et al.Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study.Am J Gastroenterol. 2006; 101: 2333-2340Google Scholar, 56Zanoni G. Navone R. Lunardi C. et al.In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes.PLoS Med. 2006; 3: e358Google Scholar were shown to favor the evolution of clinically manifest celiac disease in childhood. These observations indicate that celiac disease results from dysregulation of a usually suppressed T-cell response to gluten in a subset of carriers of HLA-DQ2 or HLA-DQ8.Table 1Non-HLA Loci of Celiac Disease SusceptibilityLoci identifiedType of study used for identificationOrigin of the cohort(s)Candidate genes (function)ReferenceCELIAC 2 5q31-q33linkage analysisItaly, Finland, Scandinavia, Europe (meta-analysis)Unknown36Babron M.C. Nilsson S. Adamovic S. et al.Meta and pooled analysis of European coeliac disease data.Eur J Hum Genet. 2003; 11: 828-834Google Scholar, 40Greco L. Corazza G. Babron M.C. et al.Genome search in celiac disease.Am J Hum Genet. 1998; 62: 669-675Google Scholar, 43Liu J. Juo S.H. Holopainen P. et al.Genomewide linkage analysis of celiac disease in Finnish families.Am J Hum Genet. 2002; 70: 51-59Google Scholar, 45Naluai A.T. Nilsson S. Gudjonsdottir A.H. et al.Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11.Eur J Hum Genet. 2001; 9: 938-944Google ScholarCELIAC 3 2q33Candidate gene approachFrance, The Netherlands, Sweden, NorwayCTLA4 (T cell response)38Djilali-Saiah I. Schmitz J. Harfouch-Hammoud E. et al.CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.Gut. 1998; 43: 187-189Google Scholar, 41Haimila K. Einarsdottir E. de Kauwe A. et al.The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.Genes Immun. 2009; 10: 151-161Google Scholar, 48van Belzen M.J. Mulder C.J. Zhernakova A. et al.CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients.Eur J Hum Genet. 2004; 12: 782-785Google ScholarCELIAC 4 19p13.1linkage analysisNetherlandMyosin IXB (Rho family guanosine triphosphatase)44Monsuur A.J. de Bakker P.I. Alizadeh B.Z. et al.Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect.Nat Genet. 2005; 37: 1341-1344Google ScholarCELIAC 5 15q11-q13linkage analysis (microsatellite)FinlandUnknown49Woolley N. Holopainen P. Ollikainen V. et al.A new locus for coeliac disease mapped to chromosome 15 in a population isolate.Hum Genet. 2002; 111: 40-45Google ScholarCELIAC 6 4q27GWAS (SNPs)United Kingdom, Netherland, Ireland, Italy, United States, ScandinaviaKIAA1109TENR (ADAD1)IL2IL2131Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar, 33van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 35Adamovic S. Amundsen S.S. Lie B.A. et al.Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families.Genes Immun. 2008; 9: 364-367Google Scholar, 39Garner C.P. Murray J.A. Ding Y.C. et al.Replication of celiac disease UK genome-wide association study results in a US population.Hum Mol Genet. 2009; 18: 4219-4225Google Scholar, 47Romanos J. Barisani D. Trynka G. et al.Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease.J Med Genet. 2009; 46: 60-63Google ScholarCELIAC 7 1q31GWAS (SNPs)United Kingdom, Netherland, Ireland, Italy, United StatesRGS1 (B-cell activation)31Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar, 33van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 39Garner C.P. Murray J.A. Ding Y.C. et al.Replication of celiac disease UK genome-wide association study results in a US population.Hum Mol Genet. 2009; 18: 4219-4225Google Scholar, 47Romanos J. Barisani D. Trynka G. et al.Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease.J Med Genet. 2009; 46: 60-63Google ScholarCELIAC 8 2q11-q12GWAS (SNPs)United Kingdom, Netherland, IrelandIL18RAPIL18R131Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar, 33van Heel D.A. Franke L. 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Fernandez-Arquero M. et al.Association of IL18RAP and CCR3 with celiac disease in the Spanish population.J Med Genet. 2009; 46: 617-619Google ScholarCELIAC 10 3q25-q26GWAS (SNPs)United Kingdom, Netherland, Ireland, Italy, United StatesIL12A31Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar, 33van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 39Garner C.P. Murray J.A. Ding Y.C. et al.Replication of celiac disease UK genome-wide association study results in a US population.Hum Mol Genet. 2009; 18: 4219-4225Google Scholar, 47Romanos J. Barisani D. 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