, Volume 55, Issue 5, pp 339–343 | Cite as

Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles

  • Andrew S. Louka
  • Benedicte A. Lie
  • Bente Talseth
  • Henry Ascher
  • Johan Ek
  • Audur H. Gudjónsdóttir
  • Ludvig M. SollidEmail author
Brief Communication


Certain HLA-DQ alleles are known to contribute to predisposition to coeliac disease (CD). The existence of additional independent risk-modifying loci in the HLA complex is still being debated. The DR3-DQ2 haplotype has been studied most, but the evidence is conflicting. The discrepancies may stem from the absence of such an effect, insufficient statistical power to detect an effect (i.e. small studies) and/or incomplete control of linkage disequilibrium (LD) to the neighbouring DQ-loci, known to elicit a strong effect. In the present study, we aimed to undertake a statistically high-powered family-based analysis, fully controlling effects of LD between the major DQ-risk haplotypes and neighbouring candidate loci. We investigated five markers on DR3-DQ2, DR5-DQ7 and DR7-DQ2 haplotypes in 327 Norwegian and Swedish families. Our primary finding was that TNF-308A (TNF2) was significantly associated on the DR3-DQ2 haplotype [stratum specific odds ratio (OR)=2.40 (1.25–4.48), Pc=0.009, where Pc=Pn and n=number of tests performed]. Furthermore, we confirmed earlier indications that LD between TNF2 and DQA1*05-DQB1*02 on the DR3 haplotype is more strongly maintained in family-based cases than family-based controls. In conclusion, we confirmed in this study, the largest of its kind, that additional CD risk factors independent of DQ2 alleles do exist on the DR3 haplotype.


Association study Coeliac disease Tumor necrosis factor 



Supported by grants from The European Commission (QLKT-1999–00037); The Norwegian Foundation for Health and Rehabilitation (EXTRA funds); Aktieselskabet Freia Chocolade Fabriks Medicinske Fond; The Foundation for Strategic Research; The Swedish Medical Research Council (K2000–27X-12568–03A); The Gothenburg Medical Society; The Swedish Society of Medicine; The Foundation of the National Board of Health and Welfare, and the Wilhelm and Martina Lundgren Research Foundation. Thanks to the families and B.M. Käck for help collecting samples. Sample collection in Norway was approved by the Regional Committee for Medical Research Ethics, and in Sweden by the Ethical Committee of The Medical Faculty of Göteborg University. All participating individuals signified their informed consent.


  1. Bouguerra F, Babron MC, Eliaou JF, Debbabi A, Clot J, Khaldi F, Greco L, Clerget-Darpoux F (1997) Synergistic effect of two HLA heterodimers in the susceptibility to celiac disease in Tunisia. Genet Epidemiol 14:413–422CrossRefPubMedGoogle Scholar
  2. De la Concha EG, Fernandez-Arquero M, Vigil P, Rubio A, Maluenda C, Polanco I, Fernandez C, Figueredo MA (2000) Celiac disease and TNF promoter polymorphisms. Hum Immunol 61:513–517PubMedGoogle Scholar
  3. Fernandez L, Fernandez-Arquero M, Gual L, Lazaro F, Maluenda C, Polanco I, Figueredo MA, De la Concha EG (2002) Triplet repeat polymorphism in the transmembrane region of the MICA gene in celiac disease. Tissue Antigens 59:219–222CrossRefPubMedGoogle Scholar
  4. Garrote JA, Arranz E, Telleria JJ, Castro J, Calvo C, Blanco-Quiros A (2002) TNF alpha and LT alpha gene polymorphisms as additional markers of celiac disease susceptibility in a DQ2-positive population. Immunogenetics 54:551–555CrossRefPubMedGoogle Scholar
  5. Karell K, Holopainen P, Mustalahti K, Collin P, Maki M, Partanen J (2002) Not all HLA DR3 DQ2 haplotypes confer equal susceptibility to coeliac disease: transmission analysis in families. Scand J Gastroenterol 37:56–61CrossRefPubMedGoogle Scholar
  6. Karell K, Louka AS, Moodie SJ, Ascher H, Clerget-Darpoux F, Greco L, Ciclitira PJ, Sollid LM, Partanen J, and members of the European Genetics Cluster on Coeliac Disease (2003) HLA types in coeliac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer. Results from the European Genetics Cluster on Coeliac Disease. Hum Immunol 64:469–477CrossRefPubMedGoogle Scholar
  7. Klitz W, Stephens JC, Grote M, Carrington M (1995) Discordant patterns of linkage disequilibrium of the peptide-transporter loci within the HLA class II region. Am J Hum Genet 57:1436–1444PubMedGoogle Scholar
  8. Lie BA, Sollid LM, Ascher H, Ek J, Akselsen HE, Ronningen KS, Thorsby E, Undlien DE (1999) A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease. Tissue Antigens 54:162–168PubMedGoogle Scholar
  9. Lie BA, Mora B, Boland A, Thorsby E, Mazzilli MC (2003) Joint report from the 13th IHWS celiac disease component. In: Hansen JA Dupont B (eds) HLA 2002. Immunobiology of the human MHC (in press)Google Scholar
  10. Lopez-Vazquez A, Rodrigo L, Fuentes D, Riestra S, Bousono C, Garcia-Fernandez S, Martinez-Borra J, Gonzalez S, Lopez-Larrea C (2002) 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 50:336–340CrossRefGoogle Scholar
  11. Louka AS, Sollid LM (2003) HLA in coeliac disease: unravelling the complex genetics of a complex disorder. Tissue Antigens 61:104–116Google Scholar
  12. Louka AS, Nilsson S, Olsson M, Talseth B, Lie BA, Ek J, Gudjónsdóttir AH, Ascher H, Sollid LM (2002) HLA in coeliac disease families: a novel test of risk modification by the other haplotype when at least one DQA1*05-DQB1*02 haplotype is carried. Tissue Antigens 60:147–154CrossRefPubMedGoogle Scholar
  13. Louka AS, Moodie SJ, Karell K, Bolognesi E, Ascher H, Greco L, Momigliano-Richiardi P, Partanen J, Ciclitira PJ, Sollid LM (2003) 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 64:350–358CrossRefPubMedGoogle Scholar
  14. McManus R, Moloney M, Borton M, Finch A, Chuan YT, Lawlor E, Weir DG, Kelleher D (1996a) Association of celiac disease with microsatellite polymorphisms close to the tumor necrosis factor genes. Hum Immunol 45:24–31Google Scholar
  15. McManus R, Wilson AG, Mansfield J, Weir DG, Duff GW, Kelleher D (1996b) TNF2, a polymorphism of the tumour necrosis-alpha gene promoter, is a component of the celiac disease major histocompatibility complex haplotype. Eur J Immunol 26:2113–2118PubMedGoogle Scholar
  16. Mearin ML, Biemond I, Pena AS, Polanco I, Vazquez C, Schreuder GT, de Vries RR, van Rood JJ (1983) HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease. Gut 24:532–537PubMedGoogle Scholar
  17. Ploski R, Ek J, Thorsby E, Sollid LM (1993) On the HLA-DQ(α1*0501, β1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201. Tissue Antigens 41:173–177PubMedGoogle Scholar
  18. Polvi A, Maki M, Collin P, Partanen J (1998) TNF microsatellite alleles a2 and b3 are not primarily associated with celiac disease in the Finnish population. Tissue Antigens 51:553–555PubMedGoogle Scholar
  19. Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, French M, Mallal S, Christiansen F (1999) The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 167:257–274PubMedGoogle Scholar
  20. Sollid LM (2002) Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2:647–655CrossRefPubMedGoogle Scholar
  21. Thomson G (1995) Mapping disease genes: family-based association studies. Am J Hum Genet 57:487–498PubMedGoogle Scholar
  22. Van Belzen MJ, Sandkuijl LA, Strengman E, Mulder CJJ, Crusius JBA, Peña AS, Pearson PL, Houwen RHJ, Wijmenga C (2000) A new locus within the MHC region strongly contributes to celiac disease. J Pediatr Gastroenterol Nutr 31:S15 [abstract 48]Google Scholar
  23. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi JK (1990) Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child 65:909–911PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Andrew S. Louka
    • 1
  • Benedicte A. Lie
    • 1
  • Bente Talseth
    • 1
  • Henry Ascher
    • 2
  • Johan Ek
    • 3
  • Audur H. Gudjónsdóttir
    • 2
  • Ludvig M. Sollid
    • 1
    Email author
  1. 1.Institute of ImmunologyUniversity of OsloOsloNorway
  2. 2.Department of PediatricsGöteborg University, The Queen Silvia Children's HospitalGöteborgSweden
  3. 3.Department of PediatricsBuskerud Hospital TrustDrammenNorway

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