Lifestyle can offset genetic predisposition for nonalcoholic fatty liver disease

Diet and lifestyle 12. may 2022 3 min Visiting Scholar Theresia Maria Schnurr Written by Morten Busch

People who are genetically predisposed to having a greater risk of developing certain diseases have reason for hope. This is the conclusion of new research on nonalcoholic fatty liver disease, the world’s most common liver disease afflicting a quarter of the world’s population. The study shows that people who are genetically predisposed to developing the disease can reduce their risk to that of people without this predisposition by losing weight and being physically active. Conversely, people with obesity who are inactive and have this genetic predisposition have a 19-fold risk of developing the disease.

Many people associate fatty liver with excessive alcohol consumption. However, 1 billion people worldwide have nonalcoholic fatty liver disease – excessive accumulation of triglycerides in the liver. Alcohol is not the cause; instead, unhealthy lifestyles, poor diet and lack of exercise are some of the risk factors. For many, the disease can eventually lead to cardiovascular disease, type 2 diabetes, other liver diseases or cancer.

“Identifying and treating people is massively important. We know that some people are genetically predisposed, but lifestyle also plays a key role. We analysed hundreds of thousands of UK Biobank participants to examine how these factors interact. We found that increasing physical activity and maintaining normal body weight are even more important for people with a high genetic risk. This group can almost offset their genetic risk by developing a healthier lifestyle,” explains Theresia M. Schnurr, a Visiting Scholar at Stanford University School of Medicine and an International Researcher at the Novo Nordisk Foundation Center for Basic Metabolic Research at University of Copenhagen, funded through a Novo Nordisk Foundation Stanford Bio-X Fellowship.

A good marker for active disease

Since there is no approved medication for nonalcoholic fatty liver disease, modifying lifestyle to lead to weight loss is the cornerstone intervention in treating people with the disease. However, the effects of physical activity, muscular fitness and weight loss may differ between individuals because of genetic variation. In the study, the researchers therefore wanted to elucidate the interactions between genetic predisposition and modifying lifestyle.

“Our idea was to combine some of the most important known factors for a large group of people to determine the influence of a person’s body weight versus being physically active. We therefore compared data for almost a quarter of a million UK Biobank participants without excessive alcohol intake. We compared their physical activity, muscular fitness, body mass index and a genetic risk score for nonalcoholic fatty liver disease to determine which factors are the most important,” says Theresia M. Schnurr.

Using the UK Biobank database, the researchers calculated a risk score based on genetic information for 77 genetic loci, which is important for whether people develop the disease or not. The database also contained data on the individuals’ body mass index, daily physical activity levels assessed using accelerometers and muscular fitness estimated by measuring handgrip strength.

“The most difficult task was to assess whether the people in the database actually had the disease, since accurate diagnosis requires a liver scan. However, blood tests gave us the figures for the activity of the enzyme alanine aminotransferase, a good marker for active liver disease since it is released into the bloodstream as liver cells are affected or die. Since we also filtered out people with a known liver disease and excessive drinkers, this was a good indicator of whether each person had nonalcoholic fatty liver disease or not,” explains Theresia M. Schnurr.

10% develop deadly liver disease

Although increased physical activity and grip strength only modestly attenuated the genetic disposition for the disease, being overweight or obese, measured by higher body mass index, markedly amplified the risk. Among those with normal weight, high physical activity and high genetic risk score, the odds of having suspected nonalcoholic fatty liver disease were only 1.6 times higher than those for the reference group with low genetic risk.

“So it seems that - at least based on our data - you can eat and exercise your way towards lowering your genetic burden that increases the risk of developing nonalcoholic fatty liver disease. Of course, biology is more complicated than that and we do not yet fully understand the complex relationship between genes and lifestyle. Conversely, among those with high genetic risk, the odds of developing the disease are 12-fold higher among participants with obesity and low physical activity versus those who maintained normal weight and high physical activity levels,” says Theresia M. Schnurr.

Unfortunately, many people who are developing nonalcoholic fatty liver disease are unaware of the ticking lifestyle bomb they are carrying around because diagnosis is difficult. The prevalence of the disease in the general population is estimated to be 20–30% in countries in the Western Hemisphere and 15% in Asian countries. Of these, an estimated 10% develop the deadly liver disease non-alcoholic steatohepatitis, and nonalcoholic fatty liver disease also significantly increases the risk of cardiovascular disease, type 2 diabetes and liver cancer.

“We are therefore working intensively to better understand the risk factors and how to better prevent people from developing nonalcoholic fatty liver disease. The new study shows that interventions to promote weight loss, including lifestyle, drug therapy and weight-loss surgery have an especially great effect among people with high genetic risk for the disease, so we hope in the future to be able to tell people based on their genetic risk score about the risk and perspectives and what lifestyle factors they can modify to avoid developing nonalcoholic fatty liver disease,” concludes Theresia M. Schnurr.

Theresia M. Schnurr is a Visiting Scholar at Stanford University School of Medicine and an International Researcher at the Novo Nordisk Foundation Cen...

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