Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide. Screening more than 4,000 individuals from an isolated region in Finland, an international research group has located a gene, called NIDDM2, that may be involved in a significant fraction of adult-onset diabetes tied to low insulin secretion. The strategy used to find this gene has important implications for genetic analysis of other complex diseases (caused by the interaction of multiple genes and the environment), as well as our understanding of the causes of human diabetes.
"One of the most exciting findings in this project was that NIDDM2 falls in the same small region of the human genome as the gene responsible for a very rare early-onset form of diabetes known as MODY3," says Dr. Eric Lander of the Whitehead Institute for Biomedical Research, one of the leaders of the project.
He adds, "We suspect that NIDDM2 and MODY3 may represent different versions of the same gene. A severe mutation in the gene may cause early onset disease (MODY3 generally appears before age 30), while a less severe mutation results in diabetes at about age 58the typical age of onset of NIDDM. Thus, a gene once believed to be associated only with a very rare disease in a few families may play a major role in adult-onset diabetes."
Localization of NIDDM2, described in the September issue of Nature Genetics, resulted from a combination of state-of-the-art gene mapping technology (including automated genetic mapping tools and a new computer software package called GENEHUNTER, developed at the Whitehead Institute), detailed clinical data maintained by government-established health centers in Finland, and an innovative diabetes research program established by Dr. Leif C. Groop of Lund University in Malmo, Sweden. Other institutional collaborators included Millennium Pharmaceuticals, Inc., of Cambridge, Mass., the Massachusetts Institute of Technology, and Helsinki University Hospital in Helsinki, Finland.
Primary Target for Gene Researchers
Diabetes has been a primary target of new gene mapping strategies because of its prevalence, and because of the potential benefits of new information about the molecular pathways involved in the disease.
Dr. Elisabeth Widen, a physician from Lund University who has spent the past year at the Whitehead/MIT Center for Genome Research, explains that NIDDM is a very complex disorder. Some cases result from a failure in insulin secretion by the pancreas, while others result from disruptions in the way fat and muscle tissues respond to insulin.
"The field of NIDDM research is still in its infancy," Dr. Widen says. "Drug development has been difficult because we still know so little about the pathways involved in the disease. We hope that by mapping and identifying new genes we can characterize these pathways and create a new foundation for diabetes therapy."
Ideal Site for Genetic Studies
The Nature Genetics authors explain that the Botnia region on the western coast of Finland is ideal for genetic studies because the population is unusually homogeneousit was settled over 1,000 years ago and there has been little immigration since the middle of the 14th centuryand it has many large, stable families. In addition, local health centers maintain excellent medical records. The scientists asked all previously identified diabetic patients in the Botnia region to complete questionnaires concerning family history and then recruited families with a particular history to participate in clinical studies.
Twenty-six families, comprising 217 individuals (120 diabetes patients and 97 unaffected relatives), were deemed to meet the research criteria: that is, they had at least three affected family members, including one patient who developed diabetes before age 60 and another before age 65.
The scientists performed a complete genome scan on all 217 subjects, analyzing DNA spelling differences at 387 sites distributed across all 46 human chromosomes. The goal was to locate one or more spelling differences that occurred with greater frequency in diabetes patients than their unaffected relatives. Such spelling differences provide crucial signposts, narrowing the search for new disease-related genes to tiny fragments of a single human chromosome.
Early Failure Leads to New Research Strategy
Dr. Melanie Mahtani, first author of the Nature Genetics paper, notes that the first genome analysis did not produce any significant results, leading the scientists to rethink their research strategy.
"Our initial failure to find diabetes susceptibility genes underscores the genetic complexity of NIDDM," Dr. Mahtani said. "We decided to try to increase the genetic homogeneity of our population even further by dividing the families into four groups based on insulin secretion levels in the diabetes patients."
Genetic analysis of the family group with the lowest insulin levels revealed the presence of a previously unsuspected diabetes susceptibility gene on chromosome 12, NIDDM2. "We were especially excited when we realized that the gene was localized to the same region previously linked to MODY3," Dr. Mahtani adds.
Dr. Widen says, "The mapping study alone taught us a great deal about diabetes. Conventional wisdom was that you couldn't subdivide diabetes patients based on insulin secretion or similar physiological measures because of the complex feedback loops involved in sugar metabolism. We showed that these subtle measurements can make a difference in understanding the disease."
Dr. Lander says that the strategy of subdividing patient populations based on physiological parameters could have important implications for genetic analysis of other complex diseases, including heart disease, hypertension, and cancer. "We have to be very clever about the way we think about these patient groups," he says. "This study demonstrates that subtle differences in disease presentation can unlock the door in the search for new disease genes."
This work was supported in part by grants from the Whitehead Institute, the National Institutes of Health, the Juselius Foundation, the Swedish Medical Research Council, the Finnish Diabetes Research Foundation, Millennium Pharmaceuticals, Inc., the Albert Pahlsson Foundation, the Novo-Nordisk Foundation, the Medical Research Council of Canada, the Medical Society of Finland, and the Medical Research Council (U.K.).