Alternative titles; symbols
DO: 0110741;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.5 | Diabetes mellitus, insulin-dependent, 2 | 125852 | Autosomal dominant | 3 | INS | 176730 |
A number sign (#) is used with this entry because of evidence that susceptibility to type 1 diabetes mellitus-2 (T1D2) is conferred by heterozygous mutation in the INS gene (176730) on chromosome 11p15.
For a phenotypic description and a discussion of genetic heterogeneity of T1D, see 222100.
Bell et al. (1984) described an association between T1D and a polymorphic region in the 5-prime flanking region of the insulin gene (INS; 176730). This polymorphism (Bell et al., 1981) arises from a variable number of tandemly repeated (VNTR) 14-bp oligonucleotides. When divided into 3 size classes, a significant association was seen between the short-length (class I) alleles and IDDM. Several studies were unable to demonstrate linkage of these VNTR alleles to IDDM in families, but this may in part be attributable to the fact that the disease-associated allele is present at high frequency in the general population. Several disease-associated polymorphisms were identified and the boundaries of association were mapped to a region of 19 kb on 11p15.5. Bain et al. (1992), Spielman et al. (1993), and Thomson et al. (1989) presented evidence supporting the insulin gene region-encoded susceptibility to type 1 diabetes.
Julier et al. (1991) studied polymorphisms of INS and neighboring loci in random diabetics, IDDM multiplex families, and controls. They found that HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kb segment spanned by the 5-prime INS VNTR and the third intron of the gene for insulinlike growth factor II (IGF2; 147470). In multiplex families the IDDM-associated alleles for polymorphisms in this region were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Julier et al. (1991) suggested that the results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility in a 19-kb region of INS-IGF2. Their approach may be useful in mapping susceptibility loci in other common diseases.
Davies et al. (1994) did a genomewide linkage screen in type I diabetes mellitus (IDDM1; 222100). A total of 18 different chromosomal regions showed some positive evidence of linkage to the disease, strongly suggesting that IDDM is inherited in a polygenic fashion. Although they determined that no genes are likely to have as large effects as IDDM1 in the major histocompatibility complex on 6p21, significant linkage was confirmed for IDDM2 on 11p15. See also IDDM10 (601942).
By 'cross-match' haplotype analysis and linkage disequilibrium mapping, Bennett et al. (1995) mapped the IDDM2 mutation to a site within the VNTR locus itself. Other polymorphisms were systematically excluded as primary disease determinants. Although they showed that the insulin gene is expressed biallelically in the adult pancreas, they found some evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. There was also a suggestion that parent-of-origin phenomena influenced transmission of IDDM2. Kennedy et al. (1995), who referred to the VNTR as the insulin-linked polymorphic region (ILPR), pointed out that the tandemly repeated sequences fall into 3 size classes and that IDDM is strongly associated with short ILPR alleles. The ILPR is located in the proximal promoter of the insulin gene, 365 bp from the transcription start site. From this location, it was initially thought that the ILPR might be an important transcriptional regulatory region. Kennedy et al. (1995) showed that the ILPR is capable of transducing a transcriptional signal in pancreatic beta cells, with a long ILPR possessing greater activity than a short ILPR. The ILPR contains numerous high-affinity binding sites for the transcription factor Pur-1 (PUR1; 600473), and transcriptional activation of Pur-1 is modulated by naturally occurring sequences in the ILPR. Thus, the authors speculated that this unique minisatellite may have important implications for type 1 diabetes.
IDDM2, or ILPR, comprises a variable number of tandemly repeating sequences related to ACAGGGGTGTGGGG. An interesting characteristic is its ability to form unusual DNA structures in vitro, presumably through formation of G-quartets. This raises the possibility that transcriptional activity of the insulin gene may be influenced by the quaternary DNA topology of IDDM2. Lew et al. (2000) showed that single nucleotide differences in the IDDM2 locus known to affect insulin transcription are correlated with ability to form unusual DNA structures. Through the design and testing of 2 high transcriptional activity ILPR repeats, Lew et al. (2000) demonstrated that both inter- and intramolecular G-quartet formation in the ILPR can influence transcriptional activity of the human insulin gene, and thus may contribute to that portion of diabetes susceptibility attributed to the IDDM2 locus.
Cordell et al. (1995) applied to insulin-dependent diabetes mellitus an extension of the maximum lod score method of Risch (1990), which allowed the simultaneous detection and modeling of 2 unlinked disease loci. The method was applied to affected-sib-pair data, and the joint effects of IDDM1 (HLA) and IDDM2, the INS VNTR, and of IDDM1 and FGF3-linked IDDM4 (600319) were assessed. In the presence of genetic heterogeneity, there seemed to be a significant advantage in analyzing more than 1 locus simultaneously. Cordell et al. (1995) stated that the effects at IDDM1 and IDDM2 were well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 followed a heterogeneity model.
The short class I VNTR alleles (26-63 repeats) predispose to IDDM, while class III alleles (140-210 repeats) have a dominant protective effect (Julier et al., 1991; Bennett et al., 1995). Bennett et al. (1995), Bennett et al. (1996), and Vafiadis et al. (1996) showed that, in human adult and fetal pancreas in vivo, class III alleles are associated with marginally lower INS mRNA levels than class I, suggesting transcriptional effects of the VNTR. Vafiadis et al. (1997) stated that these may be related to type 1 diabetes pathogenesis, as insulin is the only known beta-cell specific IDDM autoantigen. In search of a more plausible mechanism for the dominant effect of class III alleles, Vafiadis et al. (1997) analyzed expression of insulin in human fetal thymus, a critical site for tolerance induction to self proteins. Insulin was detected in all thymus tissues examined and class III VNTR alleles were associated with 2- to 3-fold higher INS mRNA levels than were class I alleles. The investigators proposed, therefore, that higher levels of thymic INS expression, facilitating immune tolerance induction, is a mechanism for the dominant protective effect of class III alleles. Similar results were simultaneously and independently reported by Pugliese et al. (1997), who pointed out that previous studies had shown that allelic variation at the insulin VNTR locus correlates with steady-state levels of INS mRNA in transfected rodent cell lines. Pugliese et al. (1997) also detected proinsulin and insulin protein in the human thymus during fetal development and childhood. VNTR alleles correlated with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs were associated with higher steady-state levels of INS mRNA expression. They suggested specifically that diabetes susceptibility and resistance associated with IDDM2 may derive from VNTR influence on INS transcription in the thymus. Higher levels of proinsulin in the thymus may promote negative selection (deletion) of insulin-specific T lymphocytes that play a critical role in the pathogenesis of type 1 diabetes.
In the Japanese population, Kawaguchi et al. (1997) confirmed an association between IDDM2 and genetic susceptibility to IDDM. The same positive association was found with insulin-dependent diabetes mellitus as that demonstrated in the Caucasian population. However, the general population showed a high frequency of disease-associated alleles, suggesting that the low incidence of IDDM generally in Japanese is not accounted for by differences at this locus.
Bennett et al. (1997) analyzed transmission of specific VNTR alleles in 1,316 families and demonstrated that a particular class I allele (26 to 63 repeats) does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. However, this paternal effect was observed only when the father's untransmitted allele was a class III (140 to more than 200 repeats). Bennett et al. (1997) noted that this allelic interaction is reminiscent of epigenetic phenomena observed in plants and in yeast. Bennett et al. (1997) stated that, if untransmitted chromosomes can have functional effects on the biologic properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
Dunger et al. (1998) tested the insulin VNTR 'locus,' which in Caucasians has 2 main alleles sizes: class I and class III (Bennett and Todd, 1996). They tested it as a functional candidate polymorphism for association of size at birth, as it has been shown to influence transcription of the INS gene. In a cohort of 758 term singletons followed longitudinally from birth to 2 years, they detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumferences (P = 0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P = 0.015) and weight (P = 0.009) at birth. The INS VNTR III/III genotype may have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease. Babies who did not show postnatal 'catch-up' or 'catch-down' growth were presumably those who had less confounding maternal uterine factors. The hypothesis of Dunger et al. (1998) was that size at birth is influenced by common genetic variation in INS expression or in a neighboring gene such as IGF2 (147470), regulated by the VNTR. Common allelic variation of the VNTR may be a component of the genetic-environmental interaction underlying the fetal origin of adult diseases such as hypertension and diabetes (Hales et al., 1991).
Ong et al. (1999) reanalyzed the INS VNTR data on 218 men born between 1920 and 1930 in whom the link between low birth weight and impaired glucose tolerance (IGT)/type II diabetes was first described (Hales et al., 1991). They found that low birth weight was more strongly related to IGT/type 2 diabetes in 'changers' than in 'nonchangers,' i.e., those subjects who showed little change in weight standard deviation score from birth to 1 year of age. Similar to the earlier study, it was in this 'nonchanger' group, who followed their genetic growth trajectory, that the association between the III/III genotype and birth weight was most apparent. Thus by incorporating data on birth weight and early postnatal growth, the association between INS VNTR III/III genotype and IGT/type II diabetes was stronger than that obtained by studies carried out without regard for birth weight and early growth. That this association was more evident in 'changers' than in 'nonchangers' indicated the important role of restraint of fetal growth according to intrauterine environment and nutrition. Fetal metabolic and endocrine adaptations to maternal nutritional restraint in utero may persist throughout life and lead to insulin resistance and increased susceptibility to type II diabetes. Selective peripheral insulin resistance could explain the III/III genotype associations with both larger size at birth and insulin resistance or type II diabetes risk. In conditions of fetal growth restraint, such as poor nutrition in pregnancy, peripheral insulin resistance may represent a fetal metabolic adaptation that diverts nutrients to protect brain and skeletal growth in utero, but may lead to disease in adulthood.
Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs7111341 at 11p15.5 (P = 4.4 x 10(-48)).
Molven et al. (2008) identified a heterozygous mutation in the INS gene (176730.0016) in a Norwegian mother and daughter with type 1 diabetes mellitus. The daughter presented with frank diabetes at 10 years of age; the mother was diagnosed at age 13. Both required treatment with insulin.
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