- Paper Report
- Open Access
IL-12: a candidate autoimmunity susceptibility gene
- Anne Barton1
© Biomed Central Ltd 2001
- Received: 15 March 2001
- Accepted: 26 July 2001
- Published: 26 July 2001
Type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]) is an autoimmune disease with both genetic and environmental susceptibility components. The major susceptibility component is the human leukocyte antigen complex (HLA) but an unknown number of, as yet, unidentified genes are also required to mediate susceptibility. The non-obese diabetic (NOD) mouse spontaneously develops IDDM and differs from non-susceptible strains in the IL12B gene. Which encodes the p40 subunit of the interleukin (IL)-12. IL-12 promotes differentiation of T cells to the Th1 subset, and it is this group of cells that are thought to be involved in cell-mediated immunity. In NOD mice, Th1 cells mediate progression to IDDM and administration of IL-12 to prediabetic NOD mice accelerates the onset of diabetes.
The IL12B gene maps to 5q33-34. Linkage to this region was demonstrated in 249 IDDM affected sibling pair (ASP) families (maximum multipoint LOD score 1.7). The evidence for linkage was increased in families where the affected siblings shared identical alleles at the HLA locus (LOD score 2.3), suggesting that susceptibility in some families is mediated by an interaction between a gene in the 5q33-34 region and HLA. Association with IL12B was replicated in an independent cohort of 238 IDDM ASP families with preferential transmission of allele 1 (the common allele) of the 3' UTR polymorphism to affected offspring. Expression of IL12B protein was significantly reduced in EBV-transformed cell lines of the 2/2 genotype compared with the 1/1 genotype, suggesting that this polymorphism could have a functional role.
Linkage analysis: MapMaker/Sibs; Association analysis: transmission disequilibrium test, transmission to sib-pair test; Gene expression: northern blot