Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene

Abstract

An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p< 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.

Associations of IGF2 ApaI RFLP and INS VNTR class I allele size with obesity

“…Many have considered the VNTR aetiological of various phenotypes, [10][11][12][13] but recently others, including the original groups, have come to question the evidence that the VNTR is an aetiological site. 23,24 The uncertainty of a conclusion of linear regression vs bimodal step obliges examination of a wider genomic region. We have analysed the distribution of IGF2 ApaI alleles with respect to INS VNTR class I alleles, and found an apparent clustering of IGF2 ApaI AA genotypes with the VNTR class I small size subclass (not shown).…”

Global Haplotype Diversity in the Human Insulin Gene Region

“…High LD was observed in each of the three non-African populations across the 7.8-kb region. The only exception is the 5Ј most distal SNP INS-1, though LD has been reported to extend over 6 kb 5Ј of this position (Doria et al 1996), suggesting that LD breakdown at INS-1 may instead have resulted from recurrent mutation or localized gene conversion at this marker rather than from crossover. The main difference between the non-African populations was reduced statistical power supporting LD in the Japanese, a consequence of 95% of chromosomes within this population belonging to lineage I.…”

“…Most studies have analyzed populations of European descent where low diversity at the minisatellite combined with strong linkage disequilibrium in flanking regions make it difficult to distinguish between etiological and associated variants (Bennett and Todd 1996;Doria et al 1996). The identification of etiological polymorphisms in the insulin region may therefore require analysis of a range of different populations, in particular those showing a greater range of haplotype diversity than that seen in Europeans.…”

Genetics of type 1 diabetes mellitus

“…[93][94][95][96][97][98][99][100][101][102] This susceptibility locus, IDDM2 [MIM 125852], has been mapped to chromosome 11p15.5, and most likely corresponds to the INS VNTR locus, 93 although it has been pointed out that the T1D association extends beyond the 4.1 kb region originally identified 97 towards the tyrosine hydroxylase gene. 103 This is important because subsequent studies including those cited above, which followed this original mapping, presumed that the 4.1 kb was the minimal region-in other words haplotypes were analysed within the 4.1 kb region and not outside it, and eventually provided substantial evidence for the insulin VNTR being the primary locus. However, without actually searching more thoroughly for associations in the TH gene and beyond, the question remains whether there may be a second susceptibility locus or in fact that the major determinant may lie outside the 4.1 kb region, and that the insulin VNTR is in LD with the true etiological variant.…”