Alternative titles; symbols
DO: 9352;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | {Diabetes mellitus, noninsulin-dependent 1} | 601283 | 3 | CAPN10 | 605286 |
A number sign (#) is used with this entry because of evidence that susceptibility to type 2 diabetes mellitus-1 (T2D1) can be conferred by mutation in the CAPN10 gene (605286) on chromosome 2q37.
For a phenotypic description and a discussion of genetic heterogeneity of type 2 diabetes mellitus, see 125853.
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.
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 2 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 2 diabetes in Mexican American, Finnish, and German populations.
Cox (2001) reviewed the evidence for implicating CAPN10 as a susceptibility gene for T2D1.
Busfield et al. (2002) studied indigenous Australian populations which, like some other populations including Mexican Americans, have an extraordinarily high frequency of type 2 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 2 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 2 diabetes identified in Mexican Americans was not significant in the Korean population.
Altshuler, D., Daly, M., Kruglyak, L. Guilt by association. Nature Genet. 26: 135-137, 2000. [PubMed: 11017062] [Full Text: https://doi.org/10.1038/79839]
Busfield, F., Duffy, D. L., Kesting, J. B., Walker, S. M., Lovelock, P. K., Good, D., Tate, H., Watego, D., Marczak, M., Hayman, N., Shaw, J. T. E. A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians. Am. J. Hum. Genet. 70: 349-357, 2002. [PubMed: 11742441] [Full Text: https://doi.org/10.1086/338626]
Cox, N. J., Frigge, M., Nicolae, D. L., Concannon, P., Hanis, C. L., Bell, G. I., Kong, A. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nature Genet. 21: 213-215, 1999. [PubMed: 9988276] [Full Text: https://doi.org/10.1038/6002]
Cox, N. J. Challenges in identifying genetic variation affecting susceptibility to type 2 diabetes: examples from studies of the calpain-10 gene. Hum. Molec. Genet. 10: 2301-2305, 2001. [PubMed: 11673414] [Full Text: https://doi.org/10.1093/hmg/10.20.2301]
Ghosh, S., Hauser, E. R., Magnuson, V. L., Valle, T., Ally, D. S., Karanjawala, Z. E., Rayman, J. B., Knapp, J. I., Musick, A., Tannenbaum, J., Te, C., Eldridge, W., and 19 others. A large sample of Finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter. J. Clin. Invest. 102: 704-709, 1998. [PubMed: 9710438] [Full Text: https://doi.org/10.1172/JCI2512]
Hanis, C. L., Boerwinkle, E., Chakraborty, R., Ellsworth, D. L., Concannon, P., Stirling, B., Morrison, V. A., Wapelhorst, B., Spielman, R. S., Gogolin-Ewens, K. J., Shephard, J. M., Williams, S. R., and 21 others. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet. 13: 161-166, 1996. [PubMed: 8640221] [Full Text: https://doi.org/10.1038/ng0696-161]
Horikawa, Y., Oda, N., Cox, N. J., Li, X., Orho-Melander, M., Hara, M., Hinokio, Y., Lindner, T. H., Mashima, H., Schwarz, P. E. H., del Bosque-Plata, L., Horikawa, Y., and 14 others. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet. 26: 163-175, 2000. Note: Erratum: Nature Genet. 26: 502 only, 2000. [PubMed: 11017071] [Full Text: https://doi.org/10.1038/79876]
Kang, E. S., Kim, H. J., Nam, M., Nam, C. M., Ahn, C. W., Cha, B. S., Lee, H. C. A novel 111/121 diplotype in the calpain-10 gene is associated with type 2 diabetes. J. Hum. Genet. 51: 629-633, 2006. [PubMed: 16721485] [Full Text: https://doi.org/10.1007/s10038-006-0410-9]