| Type 1 diabetes (T1D) is a common disorder in which autoimmune destruction of insulin-producing pancreatic beta-cells results in dependency on exogenous insulin. Genetic factors provide around half of the disease predisposition, with approximately a dozen genetic loci estimated to contribute to T1D development. In our investigation of T1D genetic susceptibility we pursued both mapping and candidate gene approaches using 372 US multiplex T1D families of Caucasian descent. A number of T1D candidate genes were investigated, with CBLB chosen for its role in an animal model of autoimmune diabetes. Seven SNP markers spanning the CBLB gene were tested for association with T1D with no significant association observed. Two other loci, IL12B and TAB2/SUMO4, were investigated following reports of their association with T1D. We were unable to replicate either a highly significant reported association of a 3' UTR SNP within IL12B, or its putative effect on transcription. Two published reports of a putative functional polymorphism within TAB2/SUMO4 association with T1D disagreed on identity of the associated allele. Testing of this marker in our sample set, of similar genetic background and of sufficient power, has not yielded significant association with T1D. In parallel with the candidate gene approach, we pursued identification of the IDDM17 locus, initially mapped in an extended Bedouin T1D pedigree to an 8cM/8mb region on 10g25. To evaluate whether IDDM17 contributes to T1D in a general population, I extended a previously reported genome-wide linkage scan by genotyping additional microsatellite markers. Modest evidence for linkage with T1D (MLS= 1.58) was obtained in the vicinity of IDDM17 . Upon fine-mapping the region, we identified seven SNPs, localized within a 200kb interval with moderate to high intermarker LD structure, that were significantly associated with T1D (p<0.01, PDT). The associated region centers on TRUB1, a human homologue of bacterial pseudouridine synthase, and contains parts of two other genes. The coding sequence of TRUB1 was screened for genetic variants, resulting in identification of two non-synonymous polymorphisms, one of which is significantly associated with T1D. Identification of the exact causative genetic variant is complicated by substantial LD within the associated region, requiring further genetic and functional analyses. |
