Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

Abstract

The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…One of the BTN3A2 SNPs, rs13218591, lost its borderline association when either the HLA-A or -B locus was included in the main effects test, whereas the other, rs11758089, remained significant after inclusion of either of the HLA class I loci. Furthermore, in the earlier T1DGC screen we have also reported association with SNPs near HLA-G, that is, rs4122198, rs1619379 and rs2394186, 25 and others have reported association with SNPs in the UBD/MAS1L region (particularly with rs1233478). 24 When conditioning on each of these SNPs (together with DRB1-DQA1-DQB1 and HLA-B), the association with the SNPs in the extended class I region remained significant and vise versa, except for the PRSS16 SNP rs9393796 when adjusting for rs2394186 (data not shown).…”

“…9 Furthermore, it indicates that our susceptibility locus maps away from the classical MHC, although additional risk loci are also believed to exist there, in particular for HLA-B. 25,[27][28][29] It is interesting to note that conditional logistic regression analyses in the T1DGC dataset showed that the associations with the PRSS16 SNPs and one of the BTN SNPs were independent of HLA-B, and also of the other class I loci. The associations with the PRSS16 SNPs also seemed independent of the earlier reported UBD and HLA-G associations, though some dependency was seen in the regression analyses between one of the HLA-G SNPs and one of the PRSS16 SNPs, even though there was hardly any LD between these SNPs when calculated on the basis of the entire T1DGC dataset.…”

“…Earlier analyses by our research group of the T1DGC families for associations within the classical MHC using HLA data and SNPs from an extensive screen (not extending into the region covered by the current study) have shown associations independent of DRB1-DQA1-DQB1 in three regions. 25 Therefore, we also added loci from these regions in the conditional logistic regression analyses ( Table 2). The associations with the two SNPs (rs9368492 and rs9393796) in the PRSS16 region were still significant after conditioning for DRB1-DQA1-DQB1 together with either HLA-A (Po0.01), HLA-B (Po0.01) or HLA-C (Po0.003).…”

“…Hence, we opted for a conditional logistic regression analysis, thus employing the main effects test in Unphased v2.403 47 with DRB1-DQA1-DQB1 as the conditional locus. The procedure for the grouping of DRB1-DQA1-DQB1 haplotypes is described in Eike et al 25 Health Authority. …”

“…As the underlying LD pattern is of great importance in this study, only individuals of Caucasian origin were used. Genotypes for the HLA loci were available through the T1DGC, and DRB1-DQA1-DQB1 haplotypes were manually recoded into one locus on the basis of the strong LD and confirmed by the transmission patterns in the families using the procedure described in Eike et al 25 …”