Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus

Abstract

The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.

Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus

“…The rationale to study the role and the interaction of these two genetic elements was: first, MHC class II genes have been shown to play a pivotal role in most autoimmune diseases and also to be associated with the endemic 13,14 and the sporadic forms [15][16][17] of PF; and, second, it is well established that autoantigens participate in the triggering of the B-and T-cell autoimmune responses in autoimmune diseases, and that polymorphism of the corresponding autoantigen can contribute to the autoimmune trait susceptibility as shown for the CHRNA gene in myasthenia gravis 3 and the insulin gene in IDDM. 22 In this association analysis involving the largest series of PF patients so far studied and 84 healthy controls, HLA-DRB1*0102, DRB1*0402 and 0406 and DRB1*1404 were shown to be significantly associated with PF. These data are consistent with results from three recent studies showing the association of the sporadic form of PF with DRB1*0102 and DRB*0404 in French Caucasians, 15 with DRB1*0402 and DRB1*1401 in Italian Caucasians 16 and with DRB1*0406 and DRB1*1401 in Japanese.…”

Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

“…It has been reported that the association between the class I allele and Type 1 diabetes is restricted to certain subclasses of the class I allele [7]. Thus, the INS-VNTR class III might contain subclasses of tentative functional alleles that confer susceptibility towards Type 2 diabetes.…”

“…DNA from 487 of the NGT control subjects, the 358 young healthy subjects and the 221 NGT offspring of whom one parent had Type 2 diabetes was genotyped using an HphI restriction enzyme digestion of PCR products obtained with the forward primer 5′-AGCAGGTCTGTTCCAAGG-3′ and the reverse primer 5′-CTTGGGTGTGTAGAAGAAGC-3′, followed by agarose electrophoresis of the digested PCR products, as previously reported [7]. The remaining samples were genotyped for the −23 HphI SNP applying a method based on mass spectrometry as described [20].…”

“…The INS-VNTR influences insulin expression in vitro [4,5], and in vivo the class III allele is reportedly associated with decreased levels of insulin mRNA in the pancreas [6,7]. In addition, the INS-VNTR affects IGF-2 transcription in human placenta [8].…”

Dopamine D4 Receptor Gene Novelty or Nonsense?

“…Pooling of alleles has been performed in some studies of other diseases, most notably insulin-dependent diabetes with the VNTR of the insulin gene, where there are over 50 alleles. However, a detailed transmission disequilibrium study of this polymorphism of the insulin gene (Bennett et al 1995) used individual allele lengths and found that the transmission of alleles with neighboring allele lengths either increased or decreased risk for disease.…”