TheInsulin-Like Growth Factor-II ReceptorGene Is Associated with Type 1 Diabetes: Evidence of a Maternal Effect

Abstract

Susceptibility to type 1 diabetes (T1D) is a complex trait, involving several loci. One of these putative loci, insulin-dependent diabetes mellitus-8 (IDDM8) at 6q, has been found to be subject to parental effects, suggesting the involvement of an imprinted gene. IGF-II receptor (IGF2R), the best-studied imprinted gene in the IDDM8 region, encodes the IGF-2 receptor, a protein involved in many biological processes, including immune function and beta-cell regeneration. Mice express only the maternal allele. In humans, the molecular IGF2R imprint (maternal-specific methylation) is present, but it affects expression in only a small subset of individuals. To examine whether IGF2R might contribute to the IDDM8 effect, we examined transmission distortion at several single nucleotide polymorphisms (SNPs) in 404 parent-offspring trios. After correcting for multiple testing, significant distortion was found at only one silent SNP on exon 16 (P = 0.002). SNPs upstream and downstream showed weak linkage disequilibrium and no transmission distortion, localizing the association to a 53-kb block within IGF2R. Interestingly, the exon 16 SNP association was limited to maternally inherited alleles. SLC22A2 and SLC22A3, two genes downstream of IGF2R that are imprinted in the mouse, showed no T1D association. Thus, we present evidence that maternal alleles at an IGF2R polymorphism are associated with T1D. It is thus possible that at some tissue or developmental stage not yet examined, IGF2R is universally imprinted.

The ACAA-insertion/deletion polymorphism at the 3′ UTR of the IGF-II receptor gene is associated with type 2 diabetes and surrogate markers of insulin resistance

“…We hypothesize that the ACAA-insertion/deletion polymorphism at the 3 0 UTR of the IGFIIR might be involved in the pathogenesis of type 2 diabetes by its regulatory functions on fetal growth and/or b cell proliferation (26). As opposed to the association of the ACAA-insertion/deletion polymorphism at the 3 0 UTR of the IGFIIR with type 2 diabetes and insulin-resistant traits described here by us, a previous study (27) showed that an IGFIIR polymorphism located at exon 16, and not the ACAAinsertion/deletion polymorphism at the 3 0 UTR, resulted in statistically significant transmission distortion in parent -offspring trios of children with type 1 diabetes. Possibly, this polymorphism influences some of the immune functions mediated by the IGF-II receptor, which has also been identified as a potential target for human autoimmune responses (28).…”

Analysis of Genes Critical for Growth Regulation Identifies Insulin-like Growth Factor 2 Receptor Variations with Possible Functional Significance as Risk Factors for Osteosarcoma

“…For instance, there is increased transmission of the G allele of Ex16+88G>A to children with insulin-dependent diabetes mellitus from mothers compared with those with the A allele (37). This disproportionate transmission of the maternal allele along with recent evidence for imprinting of IGF2R in humans (35,38) suggest that variants in IGF2R could be important in disease risk.…”

Could Epigenetics Play a Role in the Developmental Origins of Health and Disease?

“…Conversely, changes in methylation at the putatively polymorphically imprinted IGF2 receptor gene locus could lead to decreased IGF-II activity and small size at birth due to increased numbers of the sink IGF-II receptor (102,103). Similarly overexpression of RASGRF1, which regulates postnatal growth and is known to be imprinted in rodents, could explain the taller stature and higher IGF-I levels in IVF children.…”