Genetic variant endangers people with liver disease

Disease and treatment 2. mar 2021 2 min Postdoctoral Fellow Panu Luukkonen Written by Morten Busch

The number of people with liver disease has risen steadily parallel to the increase in the number of people with obesity. Globally, about 2 million people die per year from liver diseases such as cirrhosis and liver cancer. In a new study, researchers have found a specific genetic variant that doubles the risk of dying from liver disease. Screening people at high risk of liver disease for this variant can therefore identify those at higher risk of dying from the disease, motivating them to change their lifestyle.

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The liver is the body’s largest organ and one of the most important ones. It influences all the other organs and has many functions that maintain the body’s internal balance. Liver disease is therefore always serious and causes many deaths. Unfortunately, liver disease is now also so prevalent that predicting who will die from it can be difficult. When researchers saw a study of risk factors that contradicted current dogma, they decided to investigate further.

“The study described a known genetic variant that creates a deficiency of alpha-1-antitrypsin (AAT), a protein. According to current dogma, a person has to inherit this variant from both parents to increase the risk of serious complications of liver disease, but the risk turns out to double if the variant is in only one copy of the gene. People who also live with obesity have an even greater risk of dying from liver cancer or other liver diseases. This knowledge can save these people’s lives, because it can help physicians to identify patients at high risk before the disease progresses. Moreover, the carriers of this variant will have even greater motivation to change their lifestyle and thus prolong their lives,” explains main author Panu K. Luukkonen, Postdoctoral Fellow, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States.

Risk three times greater for people with obesity

The study focused on AAT, a protease inhibitor that usually neutralizes elastase, an enzyme that helps to break down fat, protein and carbohydrate after you eat. AAT deficiency is an inherited genetic variant affecting 1 in 1,500 children and can result in severe lung and liver disease. However, it has been thought that this disease only occurs if the gene has variations on both strands on identical chromosomes.

“When Karim Hamesch and Carolin Schneider and others published a study suggesting results contradicting the current dogma, we decided to investigate further. The study measured how having only one copy of the mutation affects the livers of people currently. However, their study did not examine whether that effect harmed people in the long term,” says Panu K. Luukkonen.

Panu K. Luukkonen knew that his colleagues in Helsinki, Finland had access to a large population cohort with long-term follow-up. Although he is currently studying non-alcoholic fatty liver disease in the United States, he therefore decided to join forces with Fredrik Åberg at Helsinki University Hospital and the University of Helsinki and Veikko Salomaa at the Finnish Institute for Health and Welfare.

“We studied the association between this gene variant and clinical liver-related diseases in the large FINRISK population cohort in Finland, which we could link with hospitalization, cancer and death in Finland’s registries. The result was both convincing and surprising. The risk of a serious trajectory of cancer and death doubled and, for the group with both a copy of the genetic variant and a body mass index exceeding 30, the risk tripled,” explains Panu K. Luukkonen.

Seeking the mechanisms

Overall, the new data show that having one copy of the gene variant is associated with a significantly increased risk of liver disease, but since this genetic variant is rare, looking for it in the general population makes little sense, since this requires time-consuming and expensive genetic screening. However, since this variant is assumed to cause many cases of liver disease, people at high risk of liver disease should be screened, says Panu K. Luukkonen.

“Since obesity appears to markedly modify the effect of the gene variant, physicians should try to motivate people with liver problems to change their lifestyle so that they can avoid the serious consequences of doing nothing,” says Panu K. Luukkonen.

Although Panu Luukkonen’s daily research is in a slightly different field – genetic variants associated with non-alcoholic fatty liver disease – the new results are relevant. Non-alcoholic fatty liver disease covers several disorders that all stem from the accumulation of fat in the liver and usually only among people who live with overweight.

“We have already characterized a handful of genetic variants that are associated with non-alcoholic fatty liver disease, and as we find more, we also hope to discover more about the mechanisms. Why do these genetic variations, like the one affecting AAT, lead to severe liver problems, and how is this connected with diet, obesity and alcohol consumption? We need to learn more about this before we can identify and help the people who are most severely affected and die from these liver diseases,” concludes Panu K. Luukkonen.

The Pi*MZ allele in alpha-1 antitrypsin increases liver-related outcomes in a population-based study” has been published in Gastroenterology. In 2019, the Novo Nordisk Foundation awarded a grant to Panu K. Luukkonen for the project Heterogeneity of Non-alcoholic Fatty Liver Disease in Humans.

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