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Constantin Polychronakos Full professor - Department of Pediatrics MUHC (Montreal Children’s Hospital) Director - Department of Endocrinology and Metabolism Montreal Children’s Hospital Director - Endocrine Genetics Laboratory Associate Member - Departments of Experimental Medicine and Human Genetics , McGill University The Montreal Children’s Hospital |
Research:
In the past 5 years my efforts have centered on elucidating the molecular genetics of diabetes.
A large-scale search for type 1 diabetes (T1D) susceptibility loci: Several years of attempts using the candidate-gene approach with relatively modest results (Diabetologia 49:958-961, 2006, J Med Genet 2006 43:129-32, J Med Genet. 2005 42:266-70, Nature Genetics 37:111-2, 2005, Diabetes 2007 56:270-5, Diabetes 2007 56:1174-6) came to an end with the availability of high-density genotyping arrays that permitted a genome-wide association (GWA) study on my collection of 1,300 families with type 1 diabetes. We identified two novel loci in Stage 1 (Nature 2007 Aug 2; 448(7153):591-4) In Nature’s top ten list for downloads in August 2007.
A genome-wide association study for type 2 diabetes: Facing the alarming increase of type 2 diabetes among children, I joined the Diabetes Gene Discovery Group, a collaboration between McGill, Université de Montréal and Centre National de Recherche Scientifique in Lille, France aimed at elucidating the genetics of type 2 diabetes by a GWA study in a French cohort, funded by Genome Canada and Génome Québec. Four loci were discovered in Stage 1 (Nature 445(7130):881-5), one of the first major proofs-of-principle for the GWA approach. I am corresponding author in this paper which had an accompanying News and Views write-up and was widely covered in the world media.
The insulin gene in type 1 diabetes (T1D): Following up on a previous observation that a polymorphism upstream of the insulin gene confers diabetes risk by modulating expression levels in the thymus which, we hypothesized, modulates insulin-specific T-cell tolerance (Nature Genetics 15: 289-292, 1997, front page of the Montreal Gazette) I proceeded to test predictions of this model with functional studies in humans ( Diabetes, 2005, S18-24, Proc Natl Acad Sci, 2006, 103:11683-8 and Diabetes 2007 56:709-13) and a mouse KO with thymus-specific deficiency (Diabetes 51:1383-1390, 2002). We also pinpointed the rare cells in the thymus that make insulin (Diabetes, 53:354-9, 2004) and show that insulin transcription in these cells depends on immune rather than metabolic stimuli (Diabetes 55:2595-601, 2006).
Selected Publications:
Qu H., Yang L., Montpetit A., Polychronakos C. Genetic control of alternative splicing in the TAP2 gene: Possible implication in the genetics of type 1 diabetes. Diabetes 2007 56:270-275,2007.
Qu HQ, Marchand L, Frechette R, Bacot F, Lu Y, Polychronakos C. No association of type 1 diabetes with a functional polymorphism of the LRAP gene. Molecular Immunology. 44:2145-8, 2007.
Qu HQ and Polychronakos C. Toward further mapping of the association between the IL2RA locus and type 1 diabetes. Diabetes 2007 Apr;56(4):1174-6.
Robert Sladek, Ghislain Rocheleau, Johan Rung, Christian Dina, Lishuang Shen, David Serre, Philippe Boutin, Daniel Vincent, Alexandre Belisle, Samy Hadjadj, Beverley Balkau, Barbara Heude, Guillaume Charpentier, Thomas J. Hudson, Alexandre Montpetit, Mark Prentki, Barry I. Posner, David J. Balding, DavidMeyre, Constantin Polychronakos, Philippe Froguel. A genome-wide association study identifies novel susceptibility loci for type 2 diabetes mellitus. Nature 2007 Feb 22;445(7130):881-5.
Hakonarson H, Grant SF, Bradfield JP, Marchand L, Kim CE, Glessner JT, Grabs R, Casalunovo T, Taback SP, Frackelton EC, Lawson ML, Robinson LJ, Skraban R, Lu Y, Chiavacci RM, Stanley CA, Kirsch SE, Rappoport EF, Orange JS, Monos DS, Devoto M, Qu HQ, Polychronakos C. A Genome-Wide Association Study Identifies KIAA0350 as a novel Type1 Diabetes Gene. Nature 2007 Aug 2; 448(7153):591-4.
Qu, H, Polychronakos C. The TCF7L2 locus and type 1 diabetes. BMC Med Genet 2007 Aug 3;8(1):51.