Type II Diabetes -- Genetic Factors

Type II Diabetes -- Genetic Factors

Normally, genetic studies are conducted by a classical linkage analysis using an LOD (Logarithm of Odds) score. This type of pedigreed, generational study works well if the disease is an autosomal dominant, recessive disorder. A study of this kind focuses on a particular gene locus to see if it tracks or co-segregates with the disease.

The problem with diabetes is that, even if the exact same mutation caused it in everyone, it would look different from person to person and family to family, depending on environmental influences, the genetic background it's laid upon, and modifier genes. Its expression would be variable.Furthermore, studies have shown that diabetes is not simple; it's genetically complex, involving multiple genes, and multiple gene-environment interactions.

Since classical linkage analysis doesn't work very well when studying genes in a mixed population, geneticists are moving to sib-pair analysis, called IBD - Identity by Descent. Siblings share 50% of their genes. If a gene locus has no association with a disease, it would be predicted that the siblings would share the locus 50% of the time.

One new, and somewhat controversial, method of studying the genetic component of diabetes is an Admixture Linkage Analysis. In this method, researchers view the admixed population as an F1 cross. If a disease is linked to a chromosomal locus in a genetically distinct population, it will stay in linkage association for multiple generations, until it finally sorts out through recombination. Since it's been 15 generations or so since the Europeans came over and admixed with the Native American population, now is the perfect time to do this kind of linkage analysis. The idea is that since DNA is inherited as a block, a gene locus and a marker will stay in association longer, the closer they are on the chromosome - if they are far away, the marker will fall out and they will no longer be linked.

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Major Susceptibility Locus for Type II Diabetes

There have been several different regions of the human genome associated with susceptibility to Type II diabetes. One locus on the distal part of the long arm of chromosome 2 in the human genome has been well characterized to be linked with type II diabetes in humans. Information about this locus can be obtained at:

OMIMNIDDM

"Hanis et al. (1996) performed a genome-wide search that revealed a major susceptibility locus for noninsulin dependent diabetes mellitus (125853) on chromosome 2. The study was performed on 330 affected sibpairs 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, 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."

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.; Risch, N.; Hinds, D.; Iwasaki, N.; Ogata, M.; Omori, Y.; Petzold, C.; Rietzsch, H.; Schroder, H.-E.; Schulze, J.; Cox, N. J.; Menzel, S.; Boriraj, V. V.; Chen, X.; Lim, L. R.; Lindner, T.; Mereu, L. E.; Wang, Y.-Q.; Xiang, K.; Yamagata, K.; Yang, Y.; Bell, G. I.: 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.

Genecard for diabetes mellilitus 2

Rebhan, M., Chalifa-Caspi, V., Prilusky, J., Lancet, D.: GeneCards: encyclopedia for genes, proteins and diseases. Weizmann Institute of Science, Bioinformatics Unit and Genome Center (Rehovot, Israel), 1997. GeneCard for Diabetes mellilitus type 2 (NIDDM 1)

Information about animal models for diabetes can be obtained at:

OMIMNIDDM"Discussion of the polygenic or at least digenic inheritance of diabetes in mouse and rat models with pointers to related genetic studies in humans."