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Alessandro Doria, M.D., Ph.D.

Research Summary

Genetic Factors in the Development of Diabetes and its Complications

Dr. Doria’s research is focused around the dual problems of the epidemic of type 2 diabetes in young adults and children and the acceleration of atherosclerosis that accompanies diabetes. Both illustrate how a new environment unmasks genetic susceptibilities that heretofore were silent. Dissection of these interactions can benefit us by identifying markers of predisposition to diabetes and atherosclerosis as well as novel disease pathways that can be targeted for intervention. To this end, Dr. Doria has developed a research program that draws on the large diabetic population of the Joslin Clinic and applies the tools of epidemiology and genetics.

Early-onset type 2 diabetes.

Dr. Doria’s group was the first to demonstrate the existence of forms of maturity-onset diabetes of the young (MODY) that are characterized by insulin-resistance rather than a pure insulin-secretion deficit, providing a useful Mendelian model for common, multifactorial type 2 diabetes. Through his access to the Joslin Clinic population and a national recruitment campaign, Dr. Doria has assembled a large collection (possibly the largest in the world) of extended families with an autosomal pattern of inheritance of diabetes.

Taking advantage of this unique resource, he and his collaborators have mapped a new MODY locus to chromosome 8p, where they have identified rare mutations segregating with diabetes in a proportion of families. These mutations cluster at the B-lymphocyte kinase (BLK) locus and have detrimental effects on BLK expression or activity in insulin secreting cells. Through a collaboration with Dr. Kulkarni’s group, BLK was found to be a previously unrecognized modulator of insulin synthesis and secretion that enhances the expression of key β-cell transcription factors Pdx-1 and Nkx6.1.  While this novel regulatory pathway of insulin secretion is being further characterized with the goal of finding new drug targets, Dr. Doria’s group is pursuing an additional MODY linkage signal on chromosome 4. 

Coronary artery disease in type 2 diabetes.

Dr. Doria’s research in this field has focused on the role of interindividual variability in the response of vessels to atherogenic insults. One of his earliest contributions was the demonstration that genetic variants in the genes for adiponectin and its receptor adipoR1 are critical modulators of cardiovascular risk in patients with type 2 diabetes. These findings, originally obtained at the Joslin and then replicated in populations from Italy and in the Nurses Health Study, have two implications. First, the adiponectin axis could be the target of pharmacological manipulations aimed at decreasing atherogenesis in type 2 diabetic subjects. Second, polymorphisms in the adiponectin and adiponectin receptor gene could be used to identify individuals who are at increased cardiovascular risk and may especially benefit from such preventive therapies. 

Dr. Doria has also identified variants modulating cardiovascular risk in the leptin receptor, the oxidized-LDL receptor CD36, and NF-κB inhibitor A20. More recently, he has uncovered a synergism between the CVD-predisposing variant on chromosome 9p21 and poor glycemic control in determining cardiovascular risk in type 2 diabetes. This finding illustrates the complex etiology of coronary artery disease and highlights the importance of accounting for gene-environment and gene-gene interactions in the quest for genetic factors contributing to this complication of diabetes. Dr. Doria is now extending his search for genetic determinants of coronary artery disease in type 2 diabetes to the entire genome, collaborating in this endeavor with the Nurses Health Study, the Health Professional Follow-up Study, and research groups from Europe.



Dr. Doria is an Investigator in the Section on Epidemiology and Genetics as well as Director of the Genetics Core at Joslin Diabetes Center. He is also an Associate Professor of Medicine at Harvard Medical School and an Associate Professor in the Department of Epidemiology at the Harvard School of Public Health.

He received his medical degree and his doctorate in endocrinology and metabolism from the University of Padua in Italy, and did a fellowship at Joslin Diabetes Center. Prior to coming back to Joslin as Investigator, he was a Senior Lecturer/Honorary Consultant in Endocrinology and Diabetes at Guy's Hospital and the University of London in Great Britain.  He serves frequently in national and international grant review panels and was a member of the NIH study section “Kidney, Nutrition, Obesity, and Diabetes Epidemiology” for several years. He was an associate editor of OBESITY in 2005-2007 and currently serves as an associate editor of DIABETOLOGIA. He was awarded the Michaela Modan Memorial Award by the Council on Epidemiology and Statistics of the American Diabetes Association in 2006 and 2010.

Page last updated: September 24, 2018