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One nucleotide substitution in codon 39 of HLA‐DRB4*01:01:01:01 results in a novel allele, HLA‐DRB4*01:44. [ABSTRACT FROM AUTHOR]

One nucleotide substitution in codon 213 of HLA‐DQB1*04:02:01:01 results in a new allele, HLA‐DQB1*04:02:13. [ABSTRACT FROM AUTHOR]

One nucleotide substitution in codon 90 of HLA‐C*16:02:01 results in a novel allele, HLA‐C*16:46. [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]

Type 1 diabetes is an autoimmune disease that is caused by destruction of pancreatic beta-cells. Type 1 diabetes is a heterogenic disease with environmental factors as well as genetic components. It is well established that environmental factors can exert their effects only on genetically susceptible patients. There is increasing evidence that genes outside the major histocompatibility complex (MHC) region contribute to the pathogenesis of type 1 diabetes. Cytokines, due to their role in immune regulation, seem to play a crucial role in the pathogenesis of the disease. In order to investigate the immunosuppressive action of transforming growth factor-beta1 (TGF-beta1) in type 1 diabetes, 388 patients with type 1 diabetes and 229 normal controls were genotyped for the TGF-beta1 T (29) C gene polymorphism. The TGF-beta1 T (29) C gene polymorphism was amplified using ARMS-PCR. Practical part of this work was conducted in Molecular Medicine Research Group, Peninsula Medical School, Plymouth, UK. However, statistical analyses were performed in Department of pathology, Salmaniya Medical Complex, Kingdom of Bahrain. From three different genotypes of TT, TC, and CC of the TGF-beta1 T (29) C, the TC frequency increased in patients with type 1 diabetes compared to normal controls, P value = 0.00001. The TC frequency was significantly higher in patients with diabetic nephropathy (DN) in comparison with diabetic control, P value = 0.007. Further, the CC frequency was significantly less in patients compared to healthy normal control subjects, P value = 0.005. Genetic variation at the TGF-beta1 gene polymorphism T (29) C located in codon 10 is likely to confer significant susceptibility to advanced DN in patients with T1D. This is a small case-control study in Caucasians to investigate the role of the TGF-beta1 gene polymorphism T (29) C located in codon 10 in the genetic predisposition to T1D and DN. To our knowledge, this is the first genetic report highlighting the dual effects of TGF-beta1 in the onset of T1D as well as type 1 DN and can be a good model for extensive studies.