Strong Association of Ubiquitin D (UBD)/MASIL Region Distinct from DR/DQ with Type 1A Diabetes.

There is increasing evidence for genes associated with risk for type 1A diabetes in the region of the major histocompatibility complex (MHC) other than the well-established HLA-DRB1-DQB1 genes. In our survey study, we analyzed 45 families from the Diabetes Autoimmunity Study of the Young (DAISY) with an Illumina MHC custom panel of 656 single nucleotide polymorphisms (SNPs). Analysis of all phased haplotypes from these families (67 case and 103 control haplotypes) revealed an isolated cluster of diabetes-associated SNPs (6 out of 8 SNPs with p<0.05) in a region telomeric of HLA-F, the most telomerie MHC gene analyzed. We performed a follow-up study to further verify and localize the association telomeric of HLA-F using 216 different DAISY and HBDI families and 299 SNPs spanning a 6.8 Mb region telomeric of HLA-F. In our analysis of all case versus control chromosomes with phased haplotypes, there was an isolated cluster of SNPs that was highly associated with diabetes autoimmunity (7/38 SNPs with p<0.0001, 21/38 with p<0.05). This significant cluster of SNPs was located in a 180 kb region encompassing the MAS1L and UBD genes 70 kb centromeric of the peak of association from the survey study. There were only 2 other SNPs telomeric of HLA-F with p-values less than 0.0001 (consecutive SNPs) and they were over 2 Mb telomeric of the MAS1L and UBD genes. To rule out linkage disequilibrium with classic MHC alleles (HLA-DQ, -DR, -B, -A, etc), we isolated and analyzed 95 case versus 96 control chromosomes from our data with the HLA-DQ2-DR3-BS-A 1 (8.1) haplotype, a haplotype where essentially all HLA alleles and SNPs are conserved for over 3 Mb of the classic MHC. The three most significant SNPs in the analysis of the 8.1 hapotypes were again closest to the MAS1L and UBD genes, p=<0.05. Only 2 other SNPs had a p-value less than 0.05 and both were over 1.7 Mb telomeric of the Mas1L/UBD genes. The MAS1L gene encodes a Mas-related G-protein coupled receptor. The UBD gene encodes diubiquitin, a protein expressed in B cells and dendritic cells in the pancreas and thymus. Diubiquitin has been reported to contribute to the anergic phenotype of human activated regulatory CD4(+)CD25 (hi) T cells as a downstream element of the FoxP3 induced regulatory signaling pathway. This study provides evidence that polymorphisms in the MAS1L and UBD gene region telomeric of the MHC contribute to diabetes risk and describes a method of utilizing extended MHC haplotypes to help dissect out diabetes associated MHC polymorphisms independent of DR-DQ alleles. ADA-Funded Research [ABSTRACT FROM AUTHOR]