Common gene variant increases risk of developing diabetes

Oct 23 2006

Carrying two copies of a common variant of a particular gene doubles your chances of developing diabetes and puts you in a similar risk category to being clinically obese, according to a collaborative study led by UCL (University College London) researchers.

The collaborative team led by UCL Professor Steve Humphries studied the TCF7L2 gene, which was discovered to be implicated in diabetes earlier this year by a group working in Iceland. The new study followed healthy middle-aged men in the UK for 15 years, and found that carrying a common variant of the gene increased their risk of developing diabetes by 50 per cent. Carrying two copies of the variant gene increased the risk two-fold, to nearly 100 per cent. In the population as a whole, the impact of this gene on the risk of developing diabetes is as big as the problem of being clinically obese (having a body mass index over 30).

The study, published in the Journal of Molecular Medicine, also looked at White, Indian-Asian and Afro-Caribbean diabetes patients and found that the risk for carriers of the gene was essentially the same across all groups.

Professor Steve Humphries, of the UCL Centre for Cardiovascular Genetics, said: "Although being overweight is the major risk factor for developing diabetes, it is now becoming clear that an individual's genetic makeup has a big impact on whether or not they are going to develop diabetes.

"This is the first study that has followed healthy men and shown that carrying this risk gene has such a big effect. Because it is so common, and because the risk is so high, this gene seems to be causing as many cases of diabetes in the UK as obesity, which we know is the biggest risk factor.

"Our findings point to a whole new genetic mechanism which could be putting people at high risk of diabetes, and this needs to be explored. If we could understand more about this pathway, it could be possible to develop completely new treatment methods.

"In future it might be possible to use this genetic information to identify those at high risk, but the most important things to do to avoid becoming diabetic are to eat healthily, take moderate exercise and not to become overweight."

Currently, over two million people in the UK have diabetes and another 750,000 have diabetes but are unaware of it. People with diabetes are much more likely to develop heart disease and may also have other medical problems which can lead to kidney disease and blindness.

Scientists are not yet certain of the full role of the TCF7L2 gene, but it appears to be involved in switching on and off a host of other important genes, and is probably key in the pancreas (where insulin is made to control the sugar levels in the blood), as well as in fatty tissue and the gut. The actual mutation in the gene has not yet been found, and there are likely to be several different mutations acting in different people.

It is possible that this gene could become a therapeutic target, although it would be important to target TCF7L2 only in the specific tissue necessary to reduce risk of diabetes - for example, in the insulin-making cells of the pancreas. Treatment would need to be designed to avoid interfering with the gene's important functions in other tissues, which could otherwise cause unwanted side effects.

In terms of genetic screening, it might be useful in the future to include this gene in a panel of other genes that have important effects on risk of diabetes, if people carrying TCF7L2 variants were found to need a certain drug. Such an approach is already being piloted in a form of diabetes that starts in early adulthood (MODY), where different genes cause the disease and require different treatments.

Dr Angela Wilson, Director of Research at Diabetes UK which partly funded the study, said: "The findings of this research are very exciting, as Type 2 diabetes results from a complex mix of genetic and lifestyle factors.

"If we can improve our understanding as to why people with certain genes are more likely to develop diabetes, it will help us to find ways to identify those at risk with a view to enabling them to take preventative action by adopting a healthy diet, becoming active and ensuring they do not become overweight - which is a major risk factor for diabetes.

"It also opens up new avenues of research which have the potential to lead to new treatments for people with diabetes."

http://www.ucl.ac.uk.