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Dr. Leigh Field works on locating the genes that make a person susceptible to Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM). This form of diabetes results from autoimmune destruction of the pancreatic cells that produce insulin, and occurs in about 1 in 300 children of European-ancestry by age 20. When Dr. Field first began her search for these genes in 1990, funded by the newly-created CGDN, only two genetic regions were known to contain diabetes susceptibility genes (HLA and INS, called IDDM1 and IDDM2). HLA predisposition was known since the early 1970’s, and predisposition in the insulin gene (INS) region was discovered in the mid-1980’s. She hypothesized that there must be other genes that predispose, since theoretical studies showed that HLA and INS gene sharing could not account for all of the increased risk to relatives of diabetics. So in 1990, she set out to find these other genes by performing a "genome scan" with microsatellite markers across all the chromosomes, using 250 families that had two or more diabetic children. Many of her colleagues were dubious about the value of doing such a study, reasoning that there might not BE any more diabetes genes to find. However, she and others decided to go ahead with the search, and were rewarded by finding new susceptibility genes. In 1994, Dr. Field reported the discovery of IDDM3 and IDDM4, in 1996 IDDM11, and just recently IDDM16 (new genes are given official symbols by the Human Gene Mapping Nomenclature Committee). There are less than 10 labs in the world working on identifying new diabetes susceptibility genes, and they have located at least 15-20 of them so far. All of these genes have small effects on susceptibility, and it has proven very difficult to isolate the actual genes (as opposed to just finding their chromosomal location). It is likely that these genes have small effects because they are common genes that only increase risk of diabetes, but do not by themselves cause diabetes. However, it is possible that particular combinations of these small-effect genes may have large effects on an individual person’s susceptibility. The challenges for the future are, therefore, to locate all the small-effect genes, to isolate them and elucidate their function, and to determine whether certain combinations of genes may be highly predisposing. The ultimate goal of this research is to predict which persons at are highest risk of IDDM, both in families of diabetics and in the general population, prior to destruction of pancreatic insulin-producing cells. These persons would then be specifically targeted for therapies to prevent development of diabetes. To date, preventative therapies are in research trials only (including administration of nicotinamide or low-dose insulin to high risk relatives). Identification of diabetes-predisposing genes, leading to better understanding of the disease processes, will also aid in designing other therapies which may be even more effective in preventing this devastating disease. |