Unraveling the genetics of insulin-dependent type 1A diabetes: the search must go on

Insulin-dependent type 1A diabetes results from the autoimmune destruction of pancreatic beta-cells. A targe body of evidence indicates that inherited genetic factors influence both susceptibility and resistance to the disease. At least 17 chromosomal regions have been linked to diabetes susceptibility, suggesting that type 1A diabetes is a polygenic disorder. Alleles from well-characterized susceptibility loci are commonly observed in the population and appear to have normal sequences. This suggests that susceptibility may simply derive from polymorphisms affecting the function and expression of certain proteins. There is also evidence for the existence of epistatic phenomena involving several loci and of complex parental effects reportedly modifying the transmission and expression of inherited genes. Moreover, it is an intriguing but unproven possibility that additional genetic factors or their expression may be acquired after birth, perhaps through environmental exposures. Such factors may play a key role in triggering the process leading to beta-cell destruction. This article summarizes the significant progress made during the past few years in the identification of several susceptibility loci and the understanding of the putative mechanisms by which certain loci modulate susceptibility and resistance to type 1A diabetes. Further studies are expected to lead to the full identification and characterization of susceptibility and perhaps disease genes. Such knowledge may improve prediction by genetic testing and deepen our understanding of the key mechanisms leading to the development of type 1A diabetes.