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