Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

We previously published about this research in a story titled “Study Explores Genetic Risk Factors for NAFLD” which can be found here. The study was originally published in the scientific journal Nature Genetics. You can read the abstract of the study here. 

What Happened?

This research was conducted under the US Department of Veteran Affairs Million Veteran Program. Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem that can lead to much more serious liver diseases. Around 25 percent of the human adult population is believed to have the condition, and this percentage is expected to increase even more in the coming decades. A diverse array of risk factors for the disease are known, and the goal of this study was to deepen that knowledge with a focus on discovering genetic risk factors.

This multi-ancestry genetic study included around 90,000 volunteers from the Million Veteran Program. A common method that can lead to a diagnosis of non-alcoholic fatty liver disease is a blood test to search for alanine aminotransferase (ALT). Elevated levels of this enzyme in the blood are an indicator of liver damage. All 90,000 participants had chronic ALT elevation that couldn’t be explained by other factors. There was also a 130,000 person control group, which did not have chronic elevated ALT.

The Million Veteran Program is noted as an exceptionally large and diverse biobank. This diversity gives a great advantage in research, and around 25 percent of the participants were non-white. Based on the sign of chronic ALT elevation, the researchers analyzed the genomes of participants and were able to find 77 different locations on it where certain gene variants tended to have an effect on ALT. 

These were across all different ethnicities involved in the study, which included people of African, European, Asian, and Latin ancestry. While certain genetic factors had been associated with non-alcoholic fatty liver disease, 25 of the ones identified in this study had never been identified before. The study also found one location specific to Europeans and two specific to Africans.

About Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease, also known as metabolic-associated fatty liver disease, is a condition characterized by excessive accumulation of fat in the liver accompanied by insulin resistance that isn’t the result of excess alcohol consumption. The condition has the potential to progress to a more severe form called non-alcoholic steatohepatitis (NASH) or liver cirrhosis. There isn’t necessarily a definitive direct cause of non-alcoholic fatty liver disease, but several risk factors have been identified, with the most prominent being obesity. Other factors include diet, high blood pressure, diabetes, genetics, an inactive lifestyle, and microbial imbalances. Many people with the illness do not display symptoms, but jaundice, abdominal pain, malaise, and fatigue can occur. The disease can be treated by losing weight, exercising regularly, and reducing fat in the diet. Medications or other interventions should be reserved for NASH or more serious liver disease. To learn more about non-alcoholic fatty liver disease, click here.

Why Does it Matter?

Non-alcoholic fatty liver disease is widely underdiagnosed and is becoming more and more prevalent; nearly a third of adults are expected to be impacted by the disease by the year 2030. The more widespread the disease becomes, the more widespread and serious its impacts will be. Therefore, understanding who is at the greatest risk for developing it will become more and more valuable.

The hope is that data such as that which was gathered in this study will help scientists develop a more advanced risk stratification and genetic prediction model for the illness. The findings will also lead to new avenues of research and help further the understanding of how the condition develops.

One of the top investigators of this study was Dr. Ben Voight, Corporal Michael J. Crescenz VA Medical Center, University of Pennsylvania Perelman School of Medicine, who claimed that the study “effectively tripled” the number of locations on the genome known to be associated with non-alcoholic fatty liver disease:

“For the last 10 years, the total number of robust genetic associations known could be counted on two hands. That has been unquestionably frustrating…“Genetic studies of NAFLD have been stymied owing to the difficulties and invasiveness of phenotyping patients.” – Dr. Voight