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Genetic testing: Who should do the testing and what is the role of genetic testing in the setting of celiac disease?

2005; Elsevier BV; Volume: 128; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2005.02.013

1528-0012

Edwin Liu, Marian Rewers, George S. Eisenbarth,

Diabetes and associated disorders

Celiac disease is a remarkable and common immune-mediated disorder determined by both the presence of characteristic HLA alleles (DQ2 and DQ8) and one of the best characterized environmental factors (gliadin) for any common autoimmune disease. The discovery of transglutaminase autoantibodies and the development of assays for these antibodies has allowed the identification of a large number of asymptomatic individuals with autoimmunity and intestinal biopsy evidence of celiac lesions. Further understanding of the sequelae of asymptomatic celiac disease, and the interaction between genetic susceptibility and environmental factors, are likely to alter fundamentally both genetic screening for celiac disease and its therapy. Celiac disease is a remarkable and common immune-mediated disorder determined by both the presence of characteristic HLA alleles (DQ2 and DQ8) and one of the best characterized environmental factors (gliadin) for any common autoimmune disease. The discovery of transglutaminase autoantibodies and the development of assays for these antibodies has allowed the identification of a large number of asymptomatic individuals with autoimmunity and intestinal biopsy evidence of celiac lesions. Further understanding of the sequelae of asymptomatic celiac disease, and the interaction between genetic susceptibility and environmental factors, are likely to alter fundamentally both genetic screening for celiac disease and its therapy. At the present time, public health screening is performed on a series of disorders that can be identified shortly after birth.1Liebl B. Nennstiel-Ratzel U. Roscher A. von Kries R. Data required for the evaluation of newborn screening programmes.Eur J Pediatr. 2003; 162: S57-S61Crossref PubMed Google Scholar These disorders all are relatively infrequent but include diseases such as hypothyroidism (1 in 4000 newborns)2Van Vliet G. Czernichow P. Screening for neonatal endocrinopathies rationale, methods and results.Semin Neonatol. 2004; 9: 75-85Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar and phenylketonuria (1 in 13,500–19,000 newborns), and for some areas in the United States and France even diseases such as cystic fibrosis (1 in 3300 Caucasian births) are assessed with newborn screening.3Grosskopf C. Farriaux J.P. Vidailhet M. Briard M.L. Navarro J. Turck D. Travert G. Belot V. Bloch J. Roussel P. National neonatal screening program for cystic fibrosis management and organization.Arch Pediatr. 2003; 10: 364s-369sCrossref PubMed Google Scholar The major driving force for screening is the ability to identify a treatable disorder with significant incidence such that there is a public health risk. Essentially all of the disorders are identifiable as a neonatal disorder requiring immediate therapy (eg, neonatal hypothyroidism) or are Mendelian disorders with high penetrance (eg, cystic fibrosis). The threshold for determining the cost effectiveness of screening for a particular disease is influenced very much by the infrastructure put into place for newborn screening owing to the almost universal screening for phenylketonuria and hypothyroidism. For complex genetic disorders that do not manifest in neonates and in particular immune-mediated diseases that are determined by HLA alleles, we lack a public health screening infrastructure. The question of performing genetic testing to identify children at risk for celiac disease largely depends on whether or not universal screening should be performed in the first place. Currently, the most widely used test for the presence of celiac autoimmunity is the measurement of tissue transglutaminase autoantibodies, which is highly specific and sensitive.4Schuppan D. Hahn E.G. IgA anti-tissue transglutaminase setting the stage for coeliac disease screening.Eur J Gastroenterol Hepatol. 2001; 13: 635-637Crossref PubMed Scopus (22) Google Scholar, 5Tommasini A. Not T. Kiren V. Baldas V. Santon D. Trevisiol C. Berti I. Neri E. Gerarduzzi T. Bruno I. Lenhardt A. Zamuner E. Spano A. Crovella S. Martellossi S. Torre G. Sblattero D. Marzari R. Bradbury A. Tamburlini G. Ventura A. Mass screening for coeliac disease using antihuman transglutaminase antibody assay.Arch Dis Child. 2004; 89: 512-515Crossref PubMed Scopus (201) Google Scholar Confirmation of disease is through small intestinal biopsy examination. Celiac disease is more common than any of the currently screened diseases, with an estimated incidence of 1:100–133 (Figure 1).6Fasano A. Berti I. Gerarduzzi T. Not T. Colletti R.B. Drago S. Elitsur Y. Green P.H. Guandalini S. Hill I.D. Pietzak M. Ventura A. Thorpe M. Kryszak D. Fornaroli F. Wasserman S.S. Murray J.A. Horvath K. 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: 286-292Crossref PubMed Scopus (1495) Google Scholar, 7Castano L. Blarduni E. Ortiz L. Nunez J. Bilbao J.R. Rica I. Martul P. Vitoria J.C. Prospective population screening for celiac disease high prevalence in the first 3 years of life.J Pediatr Gastroenterol Nutr. 2004; 39: 80-84Crossref PubMed Scopus (59) Google Scholar However, it is a disease that is not present (expression of tissue transglutaminase autoantibodies) until the introduction of gluten-containing foods in the diet, and usually does not manifest before age 2 years.7Castano L. Blarduni E. Ortiz L. Nunez J. Bilbao J.R. Rica I. Martul P. Vitoria J.C. Prospective population screening for celiac disease high prevalence in the first 3 years of life.J Pediatr Gastroenterol Nutr. 2004; 39: 80-84Crossref PubMed Scopus (59) Google Scholar Therefore, newborn screening for the evidence of autoantibody expression (celiac autoimmunity) likely would not be helpful. However, identifying children at risk for disease who could be selected for future screening is a possibility. There are populations at particularly high risk for developing celiac disease that include individuals with multiple different autoimmune disorders, such as type 1A diabetes, Addison's disease, and thyroid disease.8Collin P. Kaukinen K. Valimaki M. Salmi J. Endocrinological disorders and celiac disease.Endocr Rev. 2002; 23: 464-483Crossref PubMed Scopus (274) Google Scholar Figure 2 shows risk for expression of transglutaminase autoantibodies among patients and their relatives with type 1A diabetes subdivided by DR3 haplotypes containing DQ2. In first-degree relatives of patients with celiac disease, there is a 10% disease prevalence9Hogberg L. Falth-Magnusson K. Grodzinsky E. Stenhammar L. Familial prevalence of coeliac disease a twenty-year follow-up study.Scand J Gastroenterol. 2003; 38: 61-65Crossref PubMed Scopus (100) Google Scholar and monozygotic twins have a 75% concordance rate, whereas dizygotic twins do not differ from siblings,10Greco L. Romino R. Coto I. Di Cosmo N. Percopo S. Maglio M. Paparo F. Gasperi V. Limongelli M.G. Cotichini R. D'Agate C. Tinto N. Sacchetti L. Tosi R. Stazi M.A. The first large population based twin study of coeliac disease.Gut. 2002; 50: 624-628Crossref PubMed Scopus (359) Google Scholar indicating a strong genetic influence. Even though celiac disease is a complex genetic disorder, an important fact when considering genetic screening, HLA status appears to be the strongest genetic determinant of risk for celiac autoimmunity. There is a propensity for individuals with celiac disease to carry specific HLA class II alleles, which has been estimated to account for up to 40% of the genetic load.11Bevan S. Popat S. Braegger C.P. Busch A. O'Donoghue D. Falth-Magnusson K. Ferguson A. Godkin A. Hogberg L. Holmes G. Hosie K.B. Howdle P.D. Jenkins H. Jewell D. Johnston S. Kennedy N.P. Kerr G. Kumar P. Logan R.F. Love A.H. Marsh M. Mulder C.J. Sjoberg K. Stenhammer L. Houlston R.S. Contribution of the MHC region to the familial risk of coeliac disease.J Med Genet. 1999; 36: 687-690PubMed Google Scholar In affected individuals, 95% have either DQ2 (HLA-DQA1*05-DQB1*02) or DQ8 (HLA-DQA1*03-DQB1*0302), in comparison with the general population in which 39.5% have either DQ2 or DQ8.9Hogberg L. Falth-Magnusson K. Grodzinsky E. Stenhammar L. Familial prevalence of coeliac disease a twenty-year follow-up study.Scand J Gastroenterol. 2003; 38: 61-65Crossref PubMed Scopus (100) Google Scholar, 12Gudjonsdottir A.H. Nilsson S. Ek J. Kristiansson B. Ascher H. The risk of celiac disease in 107 families with at least two affected siblings.J Pediatr Gastroenterol Nutr. 2004; 38: 338-342Crossref PubMed Scopus (39) Google Scholar, 13Book L. Zone J.J. Neuhausen S.L. Prevalence of celiac disease among relatives of sib pairs with celiac disease in U.S.families. Am J Gastroenterol. 2003; 98: 377-381Crossref PubMed Scopus (88) Google Scholar These same 2 alleles determine risk for type 1A diabetes and Addison's disease, but their negative predictive values (ability in this case to exclude 60% of the population as not having risk of celiac disease) are lower. However, only 3% of individuals in the general population carrying DQ2 will develop evidence of celiac autoimmunity, suggesting that HLA typing could be used to identify increased genetic risk, but not for defining celiac disease, as is possible with many monogenic disorders. DQ2 homozygous individuals have an even higher risk for expressing transglutaminase autoantibodies and celiac disease, and among patients with type 1 diabetes almost one third of patients homozygous for DQ2 express transglutaminase autoantibodies.14Bao F. Yu L. Babu S. Wang T. Hoffenberg E.J. Rewers M. Eisenbarth G.S. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease associated transglutaminase autoantibodies.J Autoimmun. 1999; 13: 143-148Crossref PubMed Scopus (204) Google Scholar One half of these individuals have high levels of transglutaminase autoantibodies and celiac disease on intestinal biopsy examination. Polymorphisms of non-HLA genes also have been studied in celiac disease, such as MIC-A and MIC-B found in the HLA region,15Gonzalez S. Rodrigo L. Lopez-Vazquez A. Fuentes D. Agudo-Ibanez L. Rodriguez-Rodero S. Fdez-Morera J.L. Martinez-Borra J. Lopez-Larrea P.D.C. Association of MHC class I related gene B (MICB) to celiac disease.Am J Gastroenterol. 2004; 99: 676-680Crossref PubMed Scopus (30) Google Scholar, 16Lopez-Vazquez A. Rodrigo L. Fuentes D. Riestra S. Bousono C. Garcia-Fernandez S. Martinez-Borra J. Gonzalez S. Lopez-Larrea C. MHC class I chain related gene A (MICA) modulates the development of coeliac disease in patients with the high risk heterodimer DQA1*0501/DQB1*0201.Gut. 2002; 50: 336-340Crossref PubMed Scopus (87) Google Scholar, 17Rueda B. Pascual M. Lopez-Nevot M.A. Koeleman B.P. Ortega E. Maldonado J. Lopez M. Martin J. Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study.Am J Gastroenterol. 2003; 98: 359-362Crossref PubMed Scopus (23) Google Scholar and CTLA-4.18Popat S. Hearle N. Hogberg L. Braegger C.P. O'Donoghue D. Falth-Magnusson K. Holmes G.K. Howdle P.D. Jenkins H. Johnston S. Kennedy N.P. Kumar P.J. Logan R.F. Marsh M.N. Mulder C.J. Torinsson N.A. Sjoberg K. Stenhammar L. Walters J.R. Jewell D.P. Houlston R.S. Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease.Ann Hum Genet. 2002; 66: 125-137Crossref PubMed Google Scholar After correction for linkage disequilibrium with major histocompatibility complex class II alleles (eg, MIC-A) the strength of associations usually are decreased and the studies to date have not been consistent. In addition, a series of relatively small linkage (eg, sibling pair) studies to define loci determining celiac disease risk have been performed as shown in Table 1.Table 1Celiac Disease Loci Suggested by Genome ScreensStudyYearN familiesPopulation6p21.3 HLA2q33 CTLA-4 CD285qter11qter IDDM415q26 IDDM3PositiveNegativeZhong et al23Zhong F. McCombs C.C. Olson J.M. Elston R.C. Stevens F.M. McCarthy C.F. et al.An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.Nat Genet. 1996; 14: 329-333Crossref PubMed Scopus (164) Google Scholar199611Irish++/−+/−6p23 11p11 19q13.2Popat et al24Popat S. Bevan S. Braegger C.P. Busch A. O'Donoghue D. Falth-Magnusson K. et al.Genome screening of coeliac disease.J Med Genet. 2002; 39: 328-331Crossref PubMed Google Scholar199728British+−+/−6p23Greco et al25Greco L. Corazza G. Babron M.-C. Clot F. Fulchignoni-Lataud M.-C. Percopo S. et al.Genome search in celiac disease.Am J Hum Genet. 1998; 62: 669-675Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar199839 + 71 sibling pairsItalian+++−200189 sibling pairs+20035q31–33Djilali-Saiah et al26Djilali-Saiah I. Schmitz J. Harfouch-Hammoud E. Mougenot J.F. Bach J.F. Caillat-Zucman S. CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.Gut. 1998; 43: 187-189Crossref PubMed Scopus (205) Google Scholar1998101 patientsFrench++Holopainen et al27Holopainen P. Arvas M. Sistonen P. Mustalahti K. Collin P. Maki M. et al.CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease A linkage and family-based association study.Tissue Antigens. 1999; 53: 470-475Crossref PubMed Scopus (115) Google Scholar1999100Finnish++TCR2001102++−+−Yiannakou et al28Yiannakou J.Y. Brett P.M. Morris M.A. Curtis D. Mathew C. Vaughan R. et al.Family linkage study of the T-cell receptor genes in coeliac disease.Ital J Gastroenterol Hepatol. 1999; 31: 198-201PubMed Google Scholar1999British+King et al29King A.L. Yiannakou J.Y. Brett P.M. Curtis D. Morris M.A. Dearlove A.M. et al.A genome-wide family-based linkage study of coeliac disease.Ann Hum Genet. 2000; 64: 479-490Crossref PubMed Google Scholar, 30King A.L. Fraser J.S. Moodie S.J. Curtis D. Dearlove A.M. Ellis H.J. et al.Coeliac disease follow-up linkage study provides further support for existence of a susceptibility locus on chromosome 11p11.Ann Hum Genet. 2001; 65: 377-386Crossref PubMed Google Scholar200016British+10q23.1TCR200150−16q23.319q13.411p11Naluai et al31Naluai A.T. Nilsson S. Samuelsson L. Gudjonsdottir A.H. Ascher H. Ek J. 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: 350-355Crossref PubMed Scopus (105) Google Scholar2000107Swedish++NorwegianNeuhausen et al32Neuhausen S.L. Feolo M. Farnham J. Book L. Zone J.J. Linkage analysis of HLA and candidate genes for celiac disease in a North American family-based study.BMC Med Genet. 2001; 2: 12Crossref PubMed Scopus (13) Google Scholar200162United States, Utah+−−−IDDM5, 6, 7, 9, 10TCR, CD4Van Belzen et al33Van Belzen M.J. Mulder C.J. Pearson P.L. Houwen R.H. Wijmenga C. The tissue transglutaminase gene is not a primary factor predisposing to celiac disease.Am J Gastroenterol. 2001; 96: 3337-3340Crossref PubMed Scopus (9) Google Scholar2001147 patientsDutchTGAldersley et al34Aldersley M.A. Hamlin P.J. Jones P.F. Markham A.F. Robinson P.A. Howdle P.D. No polymorphism in the tissue transglutaminase gene detected in coeliac disease patients.Scand J Gastroenterol. 2000; 35: 61-63Crossref PubMed Scopus (11) Google Scholar2000BritishTGLiu et al35Liu J. Juo S.H. Holopainen P. Terwilliger J. Tong X. Grunn A. et al.Genomewide linkage analysis of celiac disease in Finnish families.Am J Hum Genet. 2002; 70: 51-59Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar200260 + 38Finnish++4p157q21Ramos-Arroyo et al36Ramos-Arroyo M.A. Feijoo E. Sanchez-Valverde F. Aranburu E. Irisarri N. Olivera J.E. et al.Heat-shock protein 70-1 and HLA class II gene polymorphisms associated with celiac disease susceptibility in Navarra (Spain).Hum Immunol. 2001; 62: 821-825Crossref PubMed Scopus (20) Google Scholar2001128 patientsSpanish+HSP70-1Lopez-Vazquez et al37Lopez-Vazquez A. Rodrigo L. Fuentes D. Riestra S. Bousono C. Garcia-Fernandez S. et al.MICA-A5.1 allele is associated with atypical forms of celiac disease in HLA-DQ2-negative patients.Immunogenetics. 2002; 53: 989-991Crossref PubMed Scopus (33) Google Scholar2002133 patientsSpanishMIC-ADe la Concha et al38de la Concha E.G. Fernandez-Arquero M. Vigil P. Rubio A. Maluenda C. Polanco I. et al.Celiac disease and TNF promoter polymorphisms.Hum Immunol. 2000; 61: 513-517Crossref PubMed Scopus (68) Google Scholar200071SpanishTNF-ALie et al39Lie B.A. Sollid L.M. Ascher H. Ek J. Akselsen H.E. Ronningen K.S. et al.A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease.Tissue Antigens. 1999; 54: 162-168Crossref PubMed Scopus (100) Google Scholar1999NorwegianD6S2223Van Belzen et al40Van Belzen M.J. Meijer J.W. Sandkuijl L.A. Bardoel A.F. Mulder C.J. Pearson P.L. et al.A major non-HLA locus in celiac disease maps to chromosome 19.Gastroenterology. 2003; 125: 1032-1041Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar2004101 sibling pairsNetherlands+19p13.16q21Gonzalez et al15Gonzalez S. Rodrigo L. Lopez-Vazquez A. Fuentes D. Agudo-Ibanez L. Rodriguez-Rodero S. Fdez-Morera J.L. Martinez-Borra J. Lopez-Larrea P.D.C. Association of MHC class I related gene B (MICB) to celiac disease.Am J Gastroenterol. 2004; 99: 676-680Crossref PubMed Scopus (30) Google Scholar2004161Spain+MIC-A5.1MIC-B0106Van Belzen et al41Van Belzen M.J. Vrolijk M.M. Meijer J.W. Crusius J.B. Pearson P.L. Sandkuijl L.A. et al.A genomewide screen in a four-generation Dutch family with celiac disease evidence for linkage to chromosomes 6 and 9.Am J Gastroenterol. 2004; 99: 466-471Crossref PubMed Scopus (22) Google Scholar20041 familyNetherlands+9p21-13TCR, T cell receptor; IDDM, insulin-dependent diabetes mellitus; HSP, heat shock protein; MIC-A, MHC class I chain-related protein A; TNF-A, tumor necrosis factor-alpha. Open table in a new tab TCR, T cell receptor; IDDM, insulin-dependent diabetes mellitus; HSP, heat shock protein; MIC-A, MHC class I chain-related protein A; TNF-A, tumor necrosis factor-alpha. Similar to studies in type 1 diabetes, for which much larger populations have been sampled, linkage studies have not identified any locus with an effect approaching that of the class II alleles of the major histocompatibility complex. At present, HLA is the primary genetic locus that can be relied on for determining risk at birth. Individuals expressing neither DQ2 nor DQ8 are at low risk.19Margaritte-Jeannin P. Babron M.C. Bourgey M. Louka A.S. Clot F. Percopo S. Coto I. Hugot J.P. Ascher H. Sollid L.M. Greco L. Clerget-Darpoux F. HLA-DQ relative risks for coeliac disease in European populations a study of the European Genetics Cluster on Coeliac Disease.Tissue Antigens. 2004; 63: 562-567Crossref PubMed Scopus (166) Google Scholar In a recent European report, only .5% of celiac patients lacked both DQ2 and DQ8. As little as .3% of tissue transglutaminase autoantibody-positive individuals and less than 1% of antibody-positive diabetic patients followed-up at our institution do not have DQ2 or DQ8. It should be noted that in the European study, the majority of the DQ2- and DQ8-negative celiac patients did in fact carry one half of the DQ2 heterodimer, often in the form of DR7 (DQB1 *02).19Margaritte-Jeannin P. Babron M.C. Bourgey M. Louka A.S. Clot F. Percopo S. Coto I. Hugot J.P. Ascher H. Sollid L.M. Greco L. Clerget-Darpoux F. HLA-DQ relative risks for coeliac disease in European populations a study of the European Genetics Cluster on Coeliac Disease.Tissue Antigens. 2004; 63: 562-567Crossref PubMed Scopus (166) Google Scholar, 20Polvi A. Arranz E. Fernandez-Arquero M. Collin P. Mäki M. Sanz A. Calvo C. Maluenda C. Westman P. de la Concha E.G. Partanen J. HLA-DQ2-negative celiac disease in Finland and Spain.Hum Immunol. 1998; 59: 169-175Crossref PubMed Scopus (100) Google Scholar Figure 3 shows the distribution of HLA in our followed-up diabetic population, and the relative rarity of celiac autoimmunity in DQ2- and DQ8-negative individuals. It is a difficult task to determine additional loci determining celiac disease and celiac disease complications such as intestinal T-cell lymphoma. Thus, at present only major histocompatibility complex can be considered for genetic analysis. In the field of type 1 diabetes, the search for genetic polymorphisms contributing to disease is relying on very large populations (thousands) and primarily case control studies. A polymorphism of the lymphocyte-tyrosine-phosphatase gene has been reported recently to be associated with type 1 diabetes. This polymorphism, the replacement of a conserved arginine with a tryptophan at codon 620, abrogates binding of the lymphocyte-tyrosine-phosphatase gene to the molecule Csk, and presumably the inhibitory influence of the lymphocyte-tyrosine-phosphatase gene on T-cell signaling.21Bottini N. Muscumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. MacMurray J. Meloni G. Lucarelli P. Pellechia M. Eisenbarth G. Comings D. Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1166) Google Scholar As reported in oral presentations, this finding (odds ratio, 1.7) now has been replicated in multiple large populations (Wicker, 2004 Immunology of Diabetes Society [IDS] meeting), and it is likely that this polymorphism will influence multiple autoimmune disorders. Another avenue to approach the genetics of complex autoimmune disorders is with the use of haplotype maps, and dense single nucleotide polymorphism (SNP) analysis, particularly for the major histocompatibility complex. It is likely that DQ alleles are themselves the major determinants of celiac disease autoimmunity within the major histocompatibility complex, but the effects are likely to be modified by other polymorphisms in this region.22Louka A.S. Moodie S.J. Karell K. Bolognesi E. Ascher H. Greco L. Momigliano-Richiardi P. Partanen J. Ciclitira P.J. Sollid L.M. A collaborative European search for non-DQA1*05-DQB1*02 celiac disease loci on HLA-DR3 haplotypes analysis of transmission from homozygous parents.Hum Immunol. 2003; 64: 350-358Crossref PubMed Scopus (26) Google Scholar In many ways celiac disease is an ideal HLA-associated disorder for consideration of public health screening. The disease is common (approximately 1% of children in the Colorado area, 8% of children with type 1A diabetes, and 33% of children who are DQ2 homozygous with type 1A diabetes) and specific HLA class II alleles (DQ2 or DQ8) are present in approximately 95% of affected individuals. The disease typically is asymptomatic and thus is not diagnosed in the majority of children. The transglutaminase autoantibody assay is inexpensive, sensitive, and specific, and small-bowel biopsy examination confirms the diagnosis. Finally, there is an effective therapy (gluten-free diet). Major caveats include the following: (1) whether the bulk of asymptomatic individuals with the disease would have morbidity/mortality from their celiac disease and whether early diagnosis and treatment is useful in preventing such morbidity/mortality; (2) only a subset of those identified with HLA-determined genetic risk will develop transglutaminase autoantibodies and biopsy examination-confirmed celiac disease (.3% with no DR3/DQ2 allele develop persistent transglutaminase autoantibody by age 7 vs approximately 3% for those with DR3/DQ2).5Tommasini A. Not T. Kiren V. Baldas V. Santon D. Trevisiol C. Berti I. Neri E. Gerarduzzi T. Bruno I. Lenhardt A. Zamuner E. Spano A. Crovella S. Martellossi S. Torre G. Sblattero D. Marzari R. Bradbury A. Tamburlini G. Ventura A. Mass screening for coeliac disease using antihuman transglutaminase antibody assay.Arch Dis Child. 2004; 89: 512-515Crossref PubMed Scopus (201) Google Scholar Public health infrastructure is not in place for screening of diseases that manifest by the expression of autoantibodies followed by diagnosed pathology in infancy, childhood, and adulthood. Genetic testing of individuals thus would involve typing of HLA, and could eliminate 60% of the population considered to be low risk (DQ2 or DQ8 negative) from needing serial autoantibody testing. Individuals considered to be at high risk for celiac disease (DQ2 or DQ8 positive) then could be selected for intervention or screening. For example, given the ability to define a higher- and lower-risk group with relatively simple class II HLA typing, an important question is whether therapy would need to be instituted in early infancy. Prospective epidemiologic studies, and in particular studies of diet headed by Jill Norris of the Celiac Disease Autoimmunity Research (CEDAR) study, are evaluating whether timing of introduction of, for instance, gliadin will influence the eventual development of celiac disease. If such a dietary influence is found and has a life-long benefit, such as altering the timing of cereal introduction, it would be a major impetus for newborn screening. On the other hand, identification of high-risk groups also selects a population for prospective screening for the development of celiac autoimmunity, enabling the institution of therapy immediately on onset of disease. In summary, celiac disease is an important candidate for public health newborn genetic screening based on HLA-DQ alleles. Outside of the newborn period, and in particular for populations at increased risk (autoimmune disorders such as type 1A diabetes and their relatives), HLA analysis can contribute to defining a population not needing repeated testing over time to identify the development of transglutaminase autoantibodies. Such testing from a public health perspective is likely to be useful given the prevalence of celiac disease and the potential for altering relatively simple factors such as the timing of introduction of gliadin. Celiac disease represents a unique disorder being considered for universal screening that likely would change the public health screening infrastructure, should it be initiated. The collaboration of the physicians and staff of the clinical division of the Barbara Davis Center is greatly appreciated.