HLA associations in type 1 diabetes: DPB1 alleles may act as markers of other HLA‐complex susceptibility genes

Wiley - Tập 61 Số 5 - Trang 344-351 - 2003
Stefan Johansson1, Benedicte A. Lie1, Flemming Pociot2, Jørn Nerup2, Anne Cambon‐Thomsen3, Ingrid Kockum4, E. Thorsby1, Dag E. Undlien1
1Institute of Immunology, Rikshospitalet University Hospital, Norway
2Steno Diabetes Center, Gentofte, Denmark
3Inserm U 558, Toulouse, France
4Dept. of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

Tóm tắt

Abstract:  Alleles at the HLA‐DQB1, ‐DQA1 and ‐DRB1 loci are major determinants for susceptibility to develop type 1 diabetes (T1D). Increasing evidence supports that also other genes in, or near, the HLA complex contribute to the HLA‐encoded risk. Alleles at the DPB1 locus have been suggested to directly influence the risk conferred by DQB1, DQA1 and DRB1 alleles, but the results are conflicting. We therefore genotyped 217 families from Norway, Denmark, Sweden and southern France to address the role of DPB1 alleles in T1D. After taking into account linkage disequilibrium (LD) with DQB1, DQA1 and DRB1 alleles, we found evidence that some DPB1 alleles are associated with modulating the risk of developing T1D. However, we show that the strong LD in the HLA complex, and the presence of extended haplotypes complicate the interpretation of the results. On DQ2‐DR3 haplotypes, both allele 3 at microsatellite D6S2223 located 5.3‐Mb telomeric of DPB1 and the extended DQ2‐DR3‐B18 haplotype display much stronger association than DPB1 alleles. When we exclude these effects, most of the apparent association of DPB1 alleles on DQ2‐DR3 haplotypes disappear. Taken together, although we cannot completely rule out an effect of some DPB1 alleles, we propose that the statistically significant, albeit weak, DPB1 associations found are most likely the result of LD with another unidentified disease‐susceptibility gene(s) in this region.

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Wiley

Tập 61 Số 5

344-351

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