A 212-kb Region on Chromosome 6q25 Containing the TAB2 Gene Is Associated With Susceptibility to Type 1 Diabetes

Abstract

The IDDM5 gene, which is identified by whole-genome searches, is located on chromosome 6q25. TAB2 (MAP3K7IP2 [mitogen-activating protein kinase kinase kinase 7 interacting protein 2]) is a potential candidate gene for type 1 diabetes because it is located on chromosome 6q25 and is involved in nuclear factor (NF)-B regulation. We have conducted familial association studies using 478 families and demonstrate that a type 1 diabetes susceptibility gene resides within a 212-kb region containing the TAB2 gene (Tsp ‫؍‬ 1.0 ؋ 10 ؊2 to 4.0 ؋ 10 ؊4 ). No amino acid polymorphisms were detected in TAB2; however, multiple single nucleotide polymorphisms (SNPs) found within 5 untranslated, 3 untranslated, and intron regions were associated with type 1 diabetes susceptibility. Two additional genes, LOC340152, a predicted gene with currently unknown function, and SMT3, which has homology to SUMO (small ubiquitin-related modifier) were found within the 212-kb region and were associated with type 1 diabetes susceptibility. Functional studies of the three genes will be required to determine their biological relevance to type 1 diabetes. However, both TAB2 and SUMO are involved in NF-B activation and may thus be involved in type 1 diabetes through apoptosis in pancreatic ␤-cells. Diabetes 53: 1890 -1893, 2004 T ype 1 diabetes is characterized by selective ␤-cell destruction, an absolute requirement for exogenous insulin, and a young, albeit heterogeneous, age of onset. The etiology and pathogenetic mechanisms of ␤-cell destruction are not completely understood, although an autoimmune process is clearly involved. The inheritance of type 1 diabetes is genetically determined, although in a complex manner. In humans, two type 1 diabetes susceptibility genes have been studied in great detail: the HLA region on chromosome 6p21, IDDM1 (1-3), and the insulin gene region, IDDM2, on chromosome 11p15 (4 -9). IDDM1 and IDDM2 contribute 42 and 10%, respectively, to the familial inheritance of the disease, and it can be further extrapolated that while other type 1 diabetes susceptibility genes exist, none can have the relatively large contribution described for IDDM1 (9,10). At present, many new putative type 1 diabetes susceptibility loci have been proposed as a result of random genome searches: IDDM3 on 15q26, IDDM4 on 11q13, IDDM5 on 6q25, IDDM6 on 18q12-q21, IDDM7 on 2q31-32, IDDM8 on 6q27, as well as additional susceptibility genes on chromosomes 1q42, 2q33-34, 3q21-25, 5q31-33, 6q21, 10p11-q11, 10q25, 14q24.3-q31, 16p11-13, 17q25, and 19q11 (11).TAB2 (MAP3K7IP2 [mitogen-activating protein kinase kinase kinase 7 interacting protein 2]) is an interesting candidate gene for type 1 diabetes because it is located on chromosome 6q25 in the IDDM5 region and is involved in nuclear factor (NF)-B regulation (12). NF-B is central to the overall immune response through its ability to activate genes coding for regulators of apoptosis and cell proliferation (13). TAB2 knockout mice are embryonic lethals in the homozygous state due to liver degenera...

Functional variants in SUMO4, TAB2, and NFκB and the risk of type 1 diabetes

“…For rs237025, results in each of the original studies indicated overtransmission of one of the two alleles to affected offspring but differed in the identity of the allele. The current study failed to confirm either of these positive findings despite having 80% power to detect the transmission rate of 56.6% reported by Owerbach et al 24 and more than 90% power to detect the transmission rate of 58.6% reported by Guo et al 18 The three studies differ methodologically in several areas, the statistical methods used to analyze the data, the selection of subjects, and the genotyping technologies, with one or more of these factors possibly relevant to discordant results obtained. The TDT is not a valid test of association when used in families with multiple affected siblings and the study by Owerbach et al, as well as the current study, employed alternative tests that can correctly account for data derived from such families.…”

“…31 In the current study, accuracy of the genotyping for the key SNP in the TAB2/SUMO4 region, rs237025, was assessed by genotyping a blinded resample of 10% of the subjects (272/2604) by an alternative method. This method, primer extension with detection by denaturing high-performance liquid chromatography, is the same as that employed by Owerbach et al 24 although the specific primer sequences used may differ.…”

“…35 Three SNPs in the TAB2/SUMO4 region were genotyped, the 163A4G (M55V) SUMO4 coding region variant and two intronic flanking markers in the TAB2 gene, rs6942381 and rs237027, both of which displayed evidence of association with T1D in the Owerbach et al study. 24 The latter two SNPs are located 57 and 1.8 kb 5 0 of rs237025, respectively. Table 1 shows results of the PDT analysis using these SNPs.…”

“…18 Two independent studies genotyped overlapping 300 and 320 kb intervals in the IDDM5 region with 18 and 15 SNP markers, respectively. 18,24 Both studies identified markers that displayed strong evidence of association with T1D in either family-based transmission/disequilibrium tests (TDT) or case-control tests. The study by Guo et al proposed a specific SNP, rs237025, as the likely causative variant.…”

“…For the putative causative variant 163A4G, Owerbach et al report increased transmission of the A allele to T1D affecteds while Guo et al observe increased transmission of the G allele; although of opposite polarity, both findings were significant. 18,24 While Guo et al reported increased NFkB transcriptional activity in association with the G allele, no significant allele specific variation in such activity was observed in a separate report by Bohren et al 25 While the predicted effects of variants in the TAB2/ SUMO4 locus on NFkB activity are mediated through biochemical interactions with other molecules, Karban et al 26 have described a functional insertion/deletion (indel) polymorphism that directly affects the expression of NFkB. The deletion allele at position À94 in the promoter of the NFKB1 gene displayed reduced binding of proteins from nuclear extracts of specific tissues in mobility shift assays and reduced transcription in luciferase assays compared to the insertion allele.…”