Help is on the way for the many people who are overweight or have type 2 diabetes. At present, they die disproportionately of blood clots in the heart or brain as a result of hardening of the arteries (atherosclerosis). If Lasse Bach Steffensen PhD of Odense University Hospital has anything to do with it, though, new medication will be developed that can reduce mortality and improve quality of life for this growing group of patients.

In his postdoc project – for which he has just received a DKK 1.8 million grant from the Danish Diabetes Academy – he aims to identify the as-yet unknown disease mechanisms causing this patient group’s increased risk of blood clots resulting from atherosclerosis.

He has a great deal of knowledge at his disposal: the growing quantity of information from large-scale human genetic studies is a vast resource for obtaining a new understanding of disease in a non-hypothesis-driven way, as Lasse Bach Steffensen explains.

‘To date, 161 places in the hereditary material have been identified as affecting the development of atherosclerosis and its complications. By combining this knowledge with newly available tissue expression data, we have found that a lot of these places in the hereditary material directly control the expression of particular genes in adipose tissue. So it looks as though adipose tissue plays a much bigger partin the development of atherosclerosis than previously assumed’, he says.

Lasse Bach Steffensen suspects that it is these adipose tissue-dependent mechanisms that are key in overweight people and those with type 2 diabetes. The plan now is to investigate whether a number of candidate genes in fat cells affect obesity, insulin resistance and atherosclerosis. This will be done using mouse models.

‘To enable this, we will be using technology on the project that lets us select for and identify adeno-associated virus variants that efficiently deliver DNA to fat cells in live mice, something that has not been possible until now. Using this unique tool, we will reduce in parallel the expression of eight candidate genes in mouse fat cells specifically, and examine how this affects adipose tissue, insulin sensitivity and the development of atherosclerosis’, he explains.

The three candidate genes with the most pronounced effect in mice will then be validated by the group in human trials from the Danish Cardiovascular Screening Trial (DANCAVAS) and the Odense Artery Biobank. Here, they will test the correlations between the candidate genes and a number of metabolism-related and cardiovascular endpoints, and investigate whether the selected candidate genes have changed expression in adipose tissue from overweight people as compared with normal-weight people.

‘We believe the unique methodology and novel design described in the proposal will be an effective way of translating the growing volume of information from large-scale genetic studies into disease mechanisms, and this will ultimately make possible new treatment strategies for these patients’, says Lasse Bach Steffensen.

CONTACT
Lasse Bach Steffensen
MSc, PhD
Odense University Hospital
https://orcid.org/0000-0001-6353-4227
lsteffensen@health.sdu.dk
25531280

‘It looks as though adipose tissue plays a much bigger part in the development of atherosclerosis than previously assumed.’