Remapping the Insulin Gene/IDDM2 Locus in Type 1 Diabetes

Abstract

Type 1 diabetes susceptibility at the IDDM2 locus was previously mapped to a variable number tandem repeat (VNTR) 5 of the insulin gene (INS). However, the observation of associated markers outside a 4.1-kb interval, previously considered to define the limits of IDDM2 association, raised the possibility that the VNTR association might result from linkage disequilibrium (LD) with an unknown polymorphism. We therefore identified a total of 177 polymorphisms and obtained genotypes for 75 of these in up to 434 pedigrees. We found that, whereas disease susceptibility did map to within the 4.1-kb region, there were two equally likely candidates for the causal variant, ؊23HphI and ؉1140A/C, in addition to the VNTR. Further analyses in 2,960 pedigrees did not support the difference in association between VNTR lineages that had previously enabled the exclusion of these two polymorphisms. Therefore, we were unable to rule out ؊23HphI and ؉1140A/C having an etiological effect. Our mapping results using robust regression methods show how precisely a variant for a common disease can be mapped, even within a region of strong LD, and specifically that IDDM2 maps to one or more of three common variants in a ϳ2-kb region of chromosome 11p15.

Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function

“…However, based on estimations of residual beta cell function, we were not able to determine whether the protective effect of class III alleles was inherited as a dominant, recessive or additive trait (p=0.08). This observation seems to be consistent with most recent genetic studies of the IDDM2 locus [5].…”

“…However, recent studies have questioned this observation [5]. It has been suggested that association of the class III alleles with higher thymic insulin mRNA expression and lower titres of insulin autoantibodies are the protective mechanisms behind reduced autoimmunity directed against beta cells [6].…”

Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15–34 years) but not in middle-aged (40–59 years) diabetic patients

“…rs689 (−23HphI variant, a surrogate for the subdivision of VNTR into class I [A] and III [T] alleles) and rs3842755, which also allows subdivision of class III into IIIA (C) and IIIB (A) alleles [29][30][31]. The SNP rs2476601 (also denoted 1858C/T) was genotyped in the PTPN22 gene [32,33].…”

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

“…The insulin gene (INS; IDDM2) and the cytotoxic T-lymphocyteassociated protein 4 (CTLA4) gene regions (IDDM12) are considered as confirmed non-HLA disease susceptibility loci [12][13][14][15][16]. Short (class I) alleles of the insulin gene 5′ variable number of tandem repeats (VNTR) are associated with increased type 1 diabetes susceptibility fitting an allele dosage model, while long class III alleles confer protection [17]. In the CTLA4 region, a number of variants, like the +49A/G, have shown disease association in various ethnic groups, while the CT60 polymorphism was identified as a candidate causative disease variant [14][15][16]18].…”