Elucidation of the genome for diabetics with DNA chips

The genome of patients with type 2 diabetes (DT2) has been elucidated, for the first time, thanks to the use of new DNA chip technologies allowing 400,000 DNA mutations to be studied simultaneously. New genes conferring a predisposition to DT2 have been identified. They include the zinc transporter of pancreatic insulin-secreting cells (ZnT8), which is a potential target for treatment. This study of the French population was carried out as a French-British-Canadian collaboration between the teams directed by Philippe Froguel (CNRS, University of Lille 2, Pasteur Institute, Imperial College London) and Rob Sladek (McGill University, Montreal, Canada). About 70% of the genetic risk of DT2 is accounted for by these new discoveries, published online in Nature on February 11 2007. This work opens up entirely new avenues of prevention and treatment for this disease.

There are more than 200 million diabetics worldwide, and it has been predicted that this number will double by 2030. This increase in the number of diabetics is linked to the obesity epidemic, which currently affects 1.1 thousand million people, including 150 million children. However, heredity also makes a major contribution to the development of DT2. Abnormalities in insulin secretion appear very early in the children of diabetic parents. These individuals become hyperglycaemic when they put on weight and are resistant to the insulin they produce. The team of Philippe Froguel was the first to identify a gene associated with DT2 — that encoding glucokinase — in 1992. Several other such genes have since been discovered, but together these genes account for only a small proportion of DT2 cases. Insufficient knowledge of the human genome and the absence of cheap, simple-to-use, rapid analytical techniques hampered progress in medical research for many years. The recent sequencing of the human genome and the establishment of a complete map of DNA variations in the human species have finally made it possible to explore genetic predisposition to DT2 in its entirety. In 2006, a revolutionary genetic analysis technique was developed in the United States. This method is based on the use of DNA chips, with a surface of only a few square centimetres, carrying almost half a million DNA mutations. Each of these chips can be used to dissect the entire genome of an individual.

Initially, DNA from non-obese patients with type 2 diabetes and a family history of the disease was compared with DNA from 669 non-diabetic subjects from the DESIR study, a prospective study run by INSERM and directed by Beverly Balkau. The key results of this first screening were then confirmed in more than 5500 French diabetic patients treated at Corbeil-Essonnes Hospital (Guillaume Charpentier) and Poitiers University Hospital (Samy Hadjadj) and in additional control subjects. These results demonstrate very strong associations between DT2 and at least four genes encoding proteins playing major roles in the development of the pancreas and of insulin-producing cells: TCF7L2, HHEX, EXT2 and SLC30A8.

• TCF7L2 and HHEX encode transcription factors (molecules regulating the activity of other genes) controlling the Wnt signalling pathway essential for cell survival. Studies in animals have shown that the absence of these genes impairs pancreatic function.

• EXT2 encodes an enzyme involved in the foetal development of several organs, including the pancreas. This enzyme also regulates Wnt signalling.

• Finally, the SLC30A8 gene encodes the ZnT8 protein, which is involved in zinc transport. This protein is involved in insulin binding in the pancreas. According to the work of the French team directed by P. Froguel and Mellitech, a biotech company from Grenoble, ZnT8 is the only molecule apart from insulin produced exclusively in the insulin-secreting beta cells of the pancreas. Zinc is a trace element present in very small amounts in the body, but essential for survival. Zinc deficiency is common in developing countries and has been associated with many diseases, including dabetes.

These four genes may account for up to 70% of the hereditary basis of DT2. Several tens of other strong "signals" have also been identified. If confirmed, these signals may complete the diabetic genome map.

This work has predictive value and has potential implications for DT2 prevention and treatment. At a time when the number of diabetics is soaring due to the increasing frequency of early, severe obesity, we need to be able to establish the profile of the young adults most at risk; this would allow personalised preventive strategies to be implemented. Some of the genes identified in this study, including the ZnT8 zinc transporter gene in particular, may be good targets for treatments to combat DT2.

These results from the analysis of very high-density DNA chips — the first in the world for a common disease like DT2 — demonstrate the validity of this approach. The method will be made available in France in March 2007, through the CNRS genotyping platform at Lille, largely funded by the Nord-pas-de-Calais Regional Council. These advances should make it possible to unravel genetic predisposition to vascular complications of diabetes and to solve the mysteries shrouding childhood obesity and certain cancers linked to obesity . The work of this French-British-Canadian team was financed principally by the Canadian government and by the province of Quebec. The DNA chips were produced at the genomics centre in Montreal.

Source : CNRS