Constantin Polychronakos, MD
Professor of Pediatrics, Experimental
Medicine and Human Genetics
Dr Polychronakos obtained his MD degree from the Aristotelian
University (Greece) in 1972. He then immigrated to Canada and trained in Paediatrics
at the University of Manitoba and Dalhousie, followed by a fellowship in Paediatric
Endocrinology at the Université de Montréal (Hôpital Sainte-Justine). He trained in
research at the McGill Polypeptide Hormone Laboratory under Dr Harvey Guyda for an
additional three years, supported by a Medical Research Council fellowship. He has
been on faculty at McGill (Department of Pediatrics, associate in Experimental
medicine and Human Genetics) since 1983, at the rank of full professor since 2000.
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Selected Scientific Contributions
In the past 5 years my efforts have centered on elucidating the
molecular genetics of diabetes. I have contributed to both the discovery of new loci
and the elucidation of the mechanism of known ones.
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 43:129-32, 2006;
J Med Genet 42:266-70, 2005; Nature Genetics 37:111-2, 2005; Diabetes 56:270-5, 2007;
Diabetes 56:1174-6, 2007) 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, funded by the Juvenile Diabetes
Foundation and the Children's Hospital of Philadelphia. We identified two novel loci
in Stage 1 (Nature 448(7153):591-4, 2007). In Nature's top ten list for August
A genome-wide association study for type 2 diabetes.
I have contributed my expertise in genome-wide studies to 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 of 3,500 cases and 3,500 controls, funded
by Genome Canada and Génome Québec. Four loci were discovered in Stage 1 (Nature
445(7130):881-5, 2007), 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 (e.g. New York Times,
Boston Globe, Daily Telegraph, Newsweek website, CBC and CTV national evening news,
front page in most major newspapers in Canada).
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 S18-24, 2005; Proc Natl Acad Sci
103:11683-8, 2006 and Diabetes 56:709-13, 2007) 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,
T1D association with CTLA4. My laboratory
contributed to the dissection of the molecular and biochemical basis on which a
haplotype at the CTLA-4 locus predisposes to T1D and other autoimmune endocrinopathies
(J Biol Chem 277:46478-86, 2002; J Clin Endocrinol Metab 89:6257-65, 2004; Genes and
Immunity 6:305-11, 2005; J Autoimmun 27:105-9, 2006).
Genomic imprinting. My laboratory published the
first report of imprinting in a human gene (Nature Genetics, 1993 with accompanying
editorial in Nature 363:94). Although I am no longer active in the field, I was
invited to write the Imprinting in Human Disease article in the Encyclopedia of
Genetics, Genomics, Proteomics and Bioinformatics (Wiley, 2006).
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