Research Project

Website:www.diabetesgenetics.ca

Summary

Insulin is a crucial hormone active in sugar and fat metabolism. Type 1 diabetes (T1D) is a complex disease, often arising in childhood, in which the immune system destroys the insulin producing cells of the pancreas. Despite insulin therapy, T1D greatly increases the probability of heart attack, stroke, blindness, and amputation, as well as shortened life expectancy. T1D afflicts 200,000 Canadians and is the result of multiple genetic risk factors and currently unknown environmental factors. This innovative research project, led by Drs. Jayne Danska and Andrew Macpherson, aims to investigate the interactions of the genetic components and environmental factors underlying T1D.

This project seeks to understand the genetic control of T1D in humans and rodent models, and to study the role of exposure to common intestinal bacteria in regulating immune system development and how such exposures affect the probability that persons at genetic risk of T1D will develop the disease.

By identifying genetic variants and bacterial exposure associated with T1D, the project team has discovered new genetic markers and has identified environmental exposures to intestinal microbes that modify inherited T1D risk.

Canada has the third highest rate of T1D in the world and the incidence is rising. T1D accounts for 10% of all diabetes cases; it cost the Canadian healthcare system $1.32 billion in 2002, and is projected to rise to $1.6 billion by 2010. This project aims to decrease the disease burden and increase the quality of life and life expectancy of persons with T1D and their families.

Dr. Jayne Danska is a Senior Scientist at Toronto’s Hospital for Sick Children and Professor in the Faculty of Medicine at the University of Toronto. Dr. Andrew Macpherson holds the Canada Research Chair in mucosal immunology at McMaster University.

This project includes integrated GE³LS research on the attitudes of adults and adolescents to predictive genetic testing for diabetes. For more information, click here.

Significant Outcomes

• The germ-free rodent facility constructed at McMaster University for this project is unique in Canada and one of only two such facilities in North America capable of performing genetic and genomic analysis of the animals.
• Project co-applicant Dr. Ake Lernmark is the principal architect of The Environmental Determinants of Diabetes in the Young (TEDDY) study, a multi-centre, 15-year longitudinal study of thousands of children with high risk for T1D. The Danska project’s important contribution to TEDDY will provide a unique opportunity for Ontario researchers to realize the benefits of what will be a landmark study of risk factors for T1D.
• When germ-free diabetes susceptible mice were subjected to a defined intestinal microbial flora an increase in incidence of diabetes was observed. Additional gender specific effects were found where male mice with intestinal microbial flora exhibited increased susceptibility to T1D.
• Preliminary data from the germ-free diabetes susceptible rat studies indicate that germ-free conditions result in later onset of diabetes.
• To explore the genetic control of T1D in humans the group tested the cord blood of newborns from mothers with and without T1D. Gene expression data indicated that the neonate’s immune system is independent of the autoimmune status of the mother.
• The team’s genetic association studies of T1D in family and population-based groups identified new loci that are important for the development of T1D as well as T1D complications such as nephropathy, cardiovascular disease, renal disease and retinal complication.
• The project also examined the views of adult relatives and older siblings of diabetics to predictive testing for T1D. These studies indicate that adolescents believe in making their own decisions on taking predictive genetic testing (but may seek parental guidance) and participate in predictive testing more for altruistic reasons.

Notable Publications
Hapfelmeier S, et al. 2010. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA Immune responses. Science 328(5986):1705-9

Paterson AD, et al. 2010. A genome-wide association study identifies a novel major locus for glycemic control in type 1 diabetes, as measured by both A1C and glucose. Diabetes 59(2): 539-49

Slack E, et al. 2009. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325(5940): 617-20

Grant, SF., et al. 2009. Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes 58(1): 290-5

Takenaka, K., Prasolava, TK., Wang, JC., Mortin-Toth, SM., Khalouei, S., Gan, OI., Dick, JE., and Danska, JS. 2007. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nature Immunology 8(12): 1313-23

Ivakine, EA., Mortin-Toth, SM., Gulban, OM., Valova, A., Canty, A., Scott, C., and Danska, JS. 2006. The idd4 locus displays sex-specific epistatic effects on type 1 diabetes susceptibility in nonobese diabetic mice. Diabetes 55(12): 3611-9