Human Genetics

C.L. Hanis, E. Boerwinkle, R. Chakraborty, D.L. Ellsworth, P. Concannon, B. Stirling, V.A. Morrison, B. Wapelhorst, R.S. Spielman, K.J. Gogolin-Ewens, J.M. Shephard, S.R. Williams, N. Risch, D. Hinds, N. Iwasaki, M. Ogata, Y. Omori, C. Petzold, H. Rietzsch, H.E. Schroder, J. Schulze, N.J. Cox, S. Menzel, V.V. Boriraj, X. Chen, L.R. Lim, T. Lindner, L.E. Mereu, Y.Q. Wang, K. Xiang, K. Yamagata, Y. Yang, G.I. Bell, "A genome-wide search for human non-insulin dependent (Type 2) diabetes genes reveals a major susceptibility locus on chromosome 2," Nature Genetics , 13 :161-6, 1996. (Cited in more than 70 publications to date) Comments by Craig L. Hanis, department of biological sciences, University of Texas Health Science Center, Houston, and Graeme I. Bell, Howard Hughes Medical Institute, department of biochemistry and molecular biology, University of Chicago GENETIC PREDICTION: University of Chicago's Graeme Bell, left, predicts that researchers will find a gene responsible for Type 2 diabetes in 1998. University of Texas Health Science Center's Craig Hanis notes that locating Mexican American sibling pairs with Type 2 diabetes made the genetic linkage study possible. Genetic factors play a role in susceptibility to non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), a disorder characterized by high blood glucose levels that, if untreated, can cause serious medical complications and lead to early death. Although this disorder is common, the number of genes involved, their exact chromosomal location, and the magnitude of their effect on NIDDM susceptibility remain unknown. Craig L. Hanis, a professor of biological sciences at the University of Texas Health Science Center in Houston, and colleagues embarked on a search for these genetic indicators. They decided to base their search in Starr County, Texas, because the county's population is 98 percent Mexican American--a group that previous epidemiological studies had indicated was three to five times as likely as the general United States population to have the condition (C.L. Hanis et al., American Journal of Epidemiology, 118 :659-72, 1983). Indeed, Hanis reports that 25 percent of the Mexican American population over 45 years of age has Type 2 diabetes. To increase the likelihood of localizing diabetes genes by linkage, the researchers decided to include only sibling pairs in the study. Staff in Starr County embarked on the quest. "We sent them out door-to-door identifying sibling pairs with Type 2 diabetes," Hanis says. "The most critical step was getting all the samples." However, the real work of genetic mapping began after all the samples were collected, when a consortium of four labs genotyped just over 500 markers. "It took four labs genotyping day in and day out to get the genetics done," Hanis recalls. The manual screening effort revealed one marker, D2S125, showing significant evidence of linkage to NIDDM. The marker, located on chromosome 2, denotes the position of a diabetes-susceptibility gene designated NIDDM1. However, the scientists have not yet found the specific gene responsible for diabetes susceptibility in this region. Hanis compares finding the region with finding a specific section or row of a lost ticket in a baseball stadium. Finding the gene is akin to finding the specific seat. The search for the Type 2 diabetes "seat" will be difficult, but not impossible, Hanis notes, since no known genes in the region are involved with the metabolic pathway--a pathway whose malfunction is associated with diabetes. "The bad news is you have to map all the genes in that region," Hanis says. "The good news is that it also suggests there are also novel metabolic pathways involved in diabetes we don't know about yet." He notes that the unknown is good news in this case because it suggests possible points for therapeutic intervention. Graeme I. Bell, a Howard Hughes Medical Institute investigator and a professor of biochemistry and molecular biology at the University of Chicago, anticipates that those points will be found soon. He predicts that "1998 is going to be the year of the diabetes gene," since the mapping has narrowed down the search. Bell notes that since the study, researchers have located mutations in two genes responsible for maturity-onset diabetes of the young (K. Yamagata et al., Nature, 384:455-8, 1996; K. Yamagata et al., Nature, 384:458-60, 1996). Bell surmises that this study has received attention because of the prevalence of the disease as well as the methodology used by the team of scientists. The analytic methods that made this study possible have already improved to the point at which the same study can now be done in a fraction of the time, and with fewer scientists involved. That technology--and the knowledge being built from it--could result in better therapies for Type 2 diabetes. "Knowing something about the nature of the genes involved may suggest biochemical pathways in the disease," Bell concludes.

Human Genetics

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April 1998

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