Joslin Investigator Details

A Harvard Medical School Affiliate

Welcome to the Joslin Research Website


	Joslin Investigator:

Dr. Alessandro Doria

Investigator Specifics:

Professional Details:

Member of Section:

Core Director:

Current Fellows, Students, or Lab Members:

Tae-Young Yang, M.D., Ph.D.

Yuan-Yuan Zhang

Past Fellows, etc.:

Maciej Borowiec

Tisha Dickey

Tonino Ercolino

Lucia Gottardo

Xiao Wei Ma

Dahlia Naqib

David Nolan

Teresa Soccio

Investigators

Adjunct Investigators

Fellows & Team Members

DERC Cores

Research Sections

Joslin Resources

Alessandro Doria, MD, PhD, MPH

Investigator and Director of the Genetics Core

Joslin Diabetes Center

Associate Professor of Medicine

Harvard Medical School

Associate Professor in the Department of Epidemiology

Harvard School of Public Health

1/7/1991 -

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 early-onset, autosomal dominant type 2 diabetes that are distinct from maturity-onset diabetes of the young (MODY). In contrast with MODY, these forms of diabetes are frequently characterized by insulin-resistance, providing a useful Mendelian model for common, multifactorial type 2 diabetes. Through my access to the Joslin Clinic population and a national recruitment campaign, Dr. Doria’s group 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, they have mapped a locus linked to early-onset, autosomal dominant type 2 diabetes to chromosome 8p, where they have identified rare mutations segregating with diabetes in a proportion of families. These mutations cluster in a narrow genomic interval containing two genes that have not been previously implicated in diabetes and which Dr. Doria is now studying from a functional point of view. While pursuing additional linkage signals on chromosome 2 and 12, Dr. Doria is also broadening his research to the study of more complex forms of early-onset type 2 diabetes, the prevalence of which has been steadily rising during the past decades to the point of reaching epidemic proportions.

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. His most important contribution is 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-B inhibitor A20. More recently, his group has uncovered a synergism between the CVD-predisposing variant on chromosome 9p21 and poor glycemic control in determining cardiovascular risk in type 2 diabetes. Dr. Doria is now extending his search for genetic determinants of coronary artery disease in type 2 diabetes to the entire genome.

Information about MODY Study

Selected References:

Doria A, Yang Y, Malecki M, Scotti S, Dreyfus J, O’Keeffe C, Orban T, Warram JH, Krolewski AS. Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes. Diabetes Care 22:253-61, 1999.

Kim SH, Ma XW, Klupa T, Powers C, Pezzolesi M, Warram JH, Rich SS, Krolewski AS, Doria A. Genetic modifiers of the age at diagnosis of diabetes (MODY3) in carriers of HNF-1alpha mutations map to chromosomes 5p15, 9q22, and 14q24. Diabetes 52:2182-2186, 2003.

Kim SH, Ma X, Weremowicz S, Ercolino T, Powers C, Mlynarski W, Bashan KA, Warram JH, Mychaleckyj J, Rich SS, Krolewski AS, Doria A: Identification of a locus for maturity-onset diabetes of the young (MODY) on chromosome 8p23. Diabetes 53:1375-1384, 2004.

Ma X, Bacci S, Mlynarski W, Gottardo L, Soccio T, Menzaghi C, Iori E, Lager RA, Shroff AR, Gervino EV, Nesto RW, Johnstone MT, Abumrad NA, Avogaro A, Trischitta V, Doria A: A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum Mol Genet 13:2197-2205, 2004.

Soccio T, Zhang YY, Bacci S, Mlynarski W, Placha G, Raggio G, Di Paola R, Marucci A, Johnstone MT, Gervino EV, Abumrad N, Klein S, Trischitta V, Doria A. Common haplotypes at the adiponectin receptor 1 (ADIPOR1) locus are associated with increased risk of coronary artery disease in type 2 diabetes. Diabetes 55:2763-2770, 2006.

Boonyasrisawat W, Eberle D, Bacci S, Zhang YY, Nolan D, Gervino EV, Johnstone MT, Trischitta V, Shoelson SE, Doria A. Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes. Diabetes 56:499-505, 2007

Doria A, Wojcik J, Xu R, Gervino EV, Hauser TH, Johnstone MT, Nolan DM, Hu FB, Warram JH. Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes. JAMA 300:2389-2397, 2008

Prudente S, Scarpelli D, Chandalia M, Zhang YY, Morini E, Del Guerra S, Perticone F, Li R, Powers C, Andreozzi F, Marchetti P, della Piccola B, Abate N, Doria A, Sesti G, Trischitta V. The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes. J Clin Endocrinol Metab 94:190-6, 2009.

Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and significance of brown adipose tissue in human adults. N Engl J Med 360:1553-6, 2009.

Borowiec M, Liew CW, Thompson R, Boonyasrisawat W, Hu J, Mlynarski WM, El Khattabi I, Kim SH, Marselli L, Rich SS, Krolewski AS, Bonner-Weir S, Sharma A, Sale M, Mychaleckyj JC, Kulkarni RN, Doria A. Mutations at the BLK locus linked to maturity onset diabetes of the young and -cell dysfunction. Proc Natl Acad Sci U S A 106:14460-5, 2009.

Biographical Sketch:

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.