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Evidence for genes associated with risk for Type 1 diabetes (T1D) in the extended region of the major histocompatibility complex (MHC) genes is accumulating. The aim of this study was to investigate the association pattern of the extended MHC region with T1D susceptibility to identify effects independent of well established DR/DQ genes. A total of 394 Europid families with T1D were genotyped for the single nucleotide polymorphism (SNP) in the olfactory receptor family 14, subfamily J, member 1 (OR14J1) gene, rs9257691, in the MHC telomeric region. The OR provides "an internal depiction of our external world" through the capture of odorant molecules in the main OR system by several large families of G-protein coupled receptors (GPCR). These receptors transduce and chemosignals into the central nervous system (CNS). This SNP was chosen to identify its association with T1D. Interestingly, OR14J1C allele was significantly associated with T1D that seems to go with DRB1*0401, Χ(2)=10.9, p=0.0003. However, by fixing both genes of DR*0401-DQB1*0302, high risk, the association of T1D with OR14J1C still existed, Χ(2)=7.4, p=0.005. The occurrence of association of the OR14J1C allele with T1D patients with DRB1*401/DQB1*0302 is an independent risk for T1D. As an accumulative report suggests the role of OR in the pathogenesis of diabetic microvascular and other diabetic complications, undoubtedly, this haplotype specific alteration of T1D risk is an independent risk for the disease and can address the promising MHC-linked gene other than DR/DQ. Moreover, there is nothing to hinder for that this might be a signal that identifies the role of OR gene in the pathogenesis of T1D in patients who are prone to diabetic complications., (Copyright © 2012. Published by Elsevier B.V.)

Objective: HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-by-descent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes., Research Design and Methods: We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium., Results: We found evidence for an association with type 1A diabetes (rs1233478, P = 1.6 x 10(-23), allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P = 1.4 x 10(-12)) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P = 0.01)., Conclusions: Polymorphisms in the region of the UBD/MAS1L genes are associated with type 1A diabetes independent of HLA class II and I alleles.

T1D results from autoimmune-mediated destruction of the pancreatic β cells, a process that is conditioned by multiple genes and environmental factors. The main genetic determinants map to the major histocompatibility complex (MHC), and in particular DR and DQ, although, genes outside the MHC contribute, including the insulin gene, PTPN22, and CTLA-4. There are remarkable differences in genetic susceptibility to T1D between populations. We believe this variation reflects differing frequencies of diabetes causative and protective alleles and haplotypes, and thus remains a major genetic influence linked to the MHC region not accounted for by DR and DQ alleles. In this article, we discuss global variations in genetic susceptibility to T1D in view of current genetic understanding. [ABSTRACT FROM AUTHOR]

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]