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Body and mind

Certain genes ensure that exercise benefits health

The health benefits of exercise are hardly breaking news. However, we still know very little about whether physical activity benefits everyone’s health equally. Previous research has suggested more than 100 genes in the human genome that could link exercise to our health. An international research team has now significantly narrowed the field down and especially focuses on four genes. The researchers hope to be able to help people who have difficulty in exercising enough to improve their health.

Many people know the feeling of looking outside on a wet grey day and considering whether they would really benefit from going for a run or cycling to the gym. Actually, this is an excellent question, because although exercise has many benefits, they vary depending on our genes. A study of 250,000 people from five continents shows that genes are crucial for determining how physical activity affects the quantities of fatty substances (lipids) in our blood.

“We knew that genes are associated with the quantities of lipids in the blood, but we were not certain how exercise modifies the genetic effects. We found four gene loci at which exercise strongly interacts with the regulation of the quantities of lipids in the blood. We will now try to understand the mechanism so that we can possibly mimic the effect and thus benefit people who have difficulty in exercising enough to improve their lipid levels,” explains a main author, Tuomas Oskari Kilpeläinen, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Cholesterol rising and falling

The new study gathered data from 86 original studies conducted on five continents. Not surprisingly, the interaction between genes, physical activity and blood lipids is extremely complex. Each original study alone was too small to find any genes that are important for this interaction, but the large international research team could get a much clearer picture by pooling the existing studies.

“Systematizing the studies so that we could, for example, compare physical activity between the studies was a major operation. Further, there are millions of genetic variants, so it was hard to find which genes are important by looking at each of these studies individually. However, when we aligned the studies, we found that responsiveness to exercise was consistently linked to four genetic loci.”

The lipids the researchers examined were the two types of cholesterol – high-density lipoprotein (HDL) and low-density lipoprotein (LDL) – and triglycerides. All three lipids are significant risk factors for cardiovascular diseases, and the body therefore needs to maintain these lipids in appropriate quantities.

“We found four gene loci at which exercise interacted with the regulation of blood cholesterol. Increased physical activity interacts with the three lipid-regulating genes CLASP1, LHX1 and SNTA1, and this results in a higher level of HDL, sometimes called “good” cholesterol. Exercise also regulates another gene, CNTNAP2, to make the body produce less of the harmful LDL cholesterol.”

Want to mimic the mechanisms

The new results may prove to be important for several reasons. First, after narrowing down the gene candidates considerably, researchers can now start studying why these genes seem to respond strongly to exercise.

“This will potentially enable us to find the people who can derive the most benefit from exercising, because their genes simply respond best to exercise and thus optimally affect their blood lipids. Conversely, other people may need higher levels of exercise or other methods to achieve the same benefits.”

Whether such knowledge can be achieved depends on future studies. Now that the researchers have established the interaction, much work lies ahead for understanding the mechanism behind it. The first step involves working with the genes in cell cultures in the laboratory to confirm the interaction and to explore how the expression of the four genes changes.

“In addition to understanding what is happening at the molecular level, we also want to examine what happens over time to individual people. Does the effect of the gene variants change over time, with exercise providing more benefits, for example, when a previously sedentary person engages in exercise training? The ultimate goal is naturally to understand the mechanisms so well that we can, for example, mimic them pharmaceutically, thereby helping people who cannot get enough exercise to improve their lipid levels.”

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity” has been published in Nature Communications. In 2010, the Novo Nordisk Foundation awarded a grant of DKK 885 million to the University of Copenhagen to establish the Novo Nordisk Foundation Center for Basic Metabolic Research, where Tuomas Oskari Kilpeläinen is employed as an Associate Professor.

Tuomas Oskari Kilpeläinen
Associate Professor
Tuomas Kilpeläinen earned his PhD at the University of Kuopio, Finland, and from 2009 to 2011 he was a post-doctoral fellow at the MRC Epidemiology Unit, University of Cambridge. In 2012 he became an assistant professor, and in 2016 an associate professor, at the Section of Metabolic Genetics of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. Since 2015, he is also an adjunct assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Tuomas’s main research interest is the identification of genetic variants contributing to the risk of obesity and type 2 diabetes and the study of how lifestyle modifies the genetic effects. Thereby he has coordinated or been actively involved in the work of a number of consortia of genome-wide association studies, and a major part of his work has focused on the identification of gene x lifestyle interactions in large-scale meta-analyses of genetic studies.