Diabetes Mellitus, Noninsulin-Dependent, 1

A number sign (#) is used with this entry because of evidence that susceptibility to noninsulin-dependent diabetes mellitus (NIDDM1) can be caused by mutation in the CAPN10 gene (605286).

For a phenotypic description and a discussion of genetic heterogeneity of noninsulin-dependent diabetes mellitus, see 125853.

Mapping

Hanis et al. (1996) performed a genomewide search that revealed a major susceptibility locus for NIDDM on chromosome 2. The study was performed on 330 affected sib pairs from Mexican American families living close to the Rio Grande River in Texas. Marker D2S125, which is located in the distal part of the long arm of chromosome 2 (2q37), showed significant evidence of linkage to NIDDM and appeared to be a major factor affecting the development of diabetes mellitus in Mexican Americans. Hanis et al. (1996) proposed that the locus be designated NIDDM1.

Using linkage analysis in a Finnish sample comprising 709 affected sib pairs from 472 sibships, Ghosh et al. (1998) excluded linkage to 2q37. They discussed possible reasons why linkage was not found and concluded that this region is unlikely to play a major role in NIDDM susceptibility in the Finnish Caucasian population.

Molecular Genetics

Genetic analyses of complex disorders such as diabetes, cardiovascular disease, asthma, hypertension, and psychiatric illnesses, when they allow for the simultaneous consideration of susceptibility from multiple chromosomal regions, may improve the ability to map the responsible genes. Cox et al. (1999) described an approach to assessing the evidence for statistical interactions between unlinked genome regions that allows multipoint allele-sharing analysis to take the evidence for linkage at one region into account in assessing the evidence for linkage over the rest of the genome. Using this method, they showed that the interaction of genes on chromosome 2 (NIDDM1) and chromosome 15 (near CYP19 (107910), which maps at 15q21.1) makes a contribution to susceptibility to type II diabetes in Mexican Americans from Starr County, Texas.

Horikawa et al. (2000) identified the CAPN10 gene in a 66-kb region in chromosome band 2q37.3, within the NIDDM1 region. Altshuler et al. (2000) described the statistical test developed by Horikawa et al. (2000), termed 'partitioning of linkage,' which demands association of an allele not just with disease but with those cases 'linked' to the locus under investigation. By applying this test, Horikawa et al. (2000) found that a SNP in intron 3 of the CAPN10 gene, designated SNP43 (605286.0001), showed a statistically significant increase in the frequency of the common G allele in patients and in addition was associated with evidence for linkage. Horikawa et al. (2000) identified 3 polymorphisms in the CAPN10 gene (SNP43; SNP19, 605286.0002; SNP63, 605286.0003) that were used to define a high-risk 112/121 haplotype combination for development of type II diabetes in Mexican American, Finnish, and German populations.

Cox (2001) reviewed the evidence for implicating CAPN10 as a susceptibility gene for NIDDM1.

Busfield et al. (2002) studied indigenous Australian populations which, like some other populations including Mexican Americans, have an extraordinarily high frequency of type II diabetes consistent with the hypothesis of the 'thrifty genotype.' In a large multigeneration pedigree segregating NIDDM in a single community, they found a maximum 2-point lod score of 2.97 at marker D2S2345, and a multipoint peak lod score of 3.9 for a location less than 1 cM from D2S2345.

In a population-based study of 454 Korean patients with type II diabetes, Kang et al. (2006) found a significant association with the 111/121 CAPN10 diplotype (odds ratio of 2.58). The high-risk 112/121 diplotype for type II diabetes identified in Mexican Americans was not significant in the Korean population.