Associate Professor in the Department of Epidemiology
Investigator, Joslin Diabetes Center, Associate Professor of Medicine, Harvard Medical School
Efforts to map genes for type 2 diabetes have been hampered by the heterogeneity of this disorder. To overcome some of these difficulties, Dr. Doria is investigating maturity onset diabetes of the young (MODY) – a subtype of diabetes for which highly informative families are available. Several candidate genes have been excluded as diabetes genes in these families by Dr. Doria. More importantly, he has identified novel loci linked with diabetes on chromosome 12q15, 8p23, and 2q37. Evidence pointing to these loci has also been found in other studies. Efforts are under way in Dr. Doria’s laboratory to identify which genes in these regions are responsible for diabetes. Although insulin deficiency characterizes the early-onset families with a mutation in a known gene (for example, HNF-1 alpha), the majority of families without a known mutation are characterized by insulin-resistance. Thus, identifying these genes carries with it the promise to provide insights into the etiology of more common forms of type 2 diabetes, which are also characterized by insulin-resistance.
In another approach to identify insulin-resistance genes, Dr. Doria participates to the Diabetes Genome Anatomy Project (DGAP) – an initiative headed by Dr. C. Ronald Kahn involving investigators from multiple institutions in the Boston area. As part of this project, Dr. Doria’s team is investigating candidate genes that are identified by other DGAP investigators as differentially expressed in insulin-resistance states. Associations between genetic variants and the insulin-resistance syndrome have been thus far demonstrated for the adiponectin and CD36 genes.
Since insulin-resistance and its associated abnormalities are also potent cardiovascular risk factors, Dr. Doria is also engaged in the search for genes that influence susceptibility to macrovascular complications in type 2 diabetes. Family studies have shown that genetic factors play an important role in the development of atherosclerosis. Dr. Doria has recently started to investigate the hypothesis that variability in genes involved in the atherosclerotic process itself may regulate the magnitude, the modality, and the timeframe of the arterial wall reaction to atherogenic factors such as insulin-resistance and diabetes. To identify these genes, he and his group are recruiting a large group of type 2 diabetic probands with coronary artery disease (CAD) and type 2 diabetic controls without CAD. Such individuals are being identified at the Joslin Clinic and at the BIDMC. The focus of this association study is on genes coding for adipokines and for molecules involved in the LDL oxidation pathway. Positive results are being validated through a collaboration with Dr. Frank Hu at the Harvard School of Public Health, who has access to large prospective studies. Other genes related to inflammatory processes are pursued through collaborations with the Reynold Cardiovascular Research Center directed by Dr. Peter Libby at the BWH.
MD PhD MPH