Research highlights the new genetic variations and pediatric NAFLD severity

In two overlapping studies, a multidisciplinary group of researchers under the direction of experts at the University of California San Diego School of Medicine have advanced investigations into the genetic causes of nonalcoholic fatty liver disease (NAFLD) in children. They have identified numerous gene variants, some of which were previously unknown, which increase the risk of developing NAFLD and those that are linked to the severity of the liver disease.

The research results were published in the journal Hepatology on June 25^th, 2022, online issue.

NAFLD is a condition where the liver’s normal function is hindered by the abnormally big fat droplets that are stored by the liver cells. It can worsen cirrhosis and liver cancer, as well as liver inflammation and a condition known as nonalcoholic steatohepatitis (NASH).

According to the American Liver Foundation, 10% of all children in the U.S. have NAFLD, and since they will have it for most of their life, they are more likely to have issues like needing a liver transplant as teenagers. A higher risk of cardiovascular disease, type 2 diabetes, and adult mortality is also linked to pediatric NAFLD.

Single nucleotide polymorphisms sometimes referred to as SNPs, are discrete genetic variants of NAFLD that have been linked to specific DNA sequence sites. The work has not been extensive though. The new research, known as the Genetics of Obesity Associated Liver Steatosis (GOALS) investigations, was created to more thoroughly and comprehensively search for pertinent SNPs in young people.

In the first analysis of the genetic risk of NAFLD transmission, 252 family trios were examined (mother, father, and child with biopsy-proven NAFLD). In the second, researchers looked at 822 kids with biopsy-proven NAFLD to explore the relationship between SNPs and the severity of the condition.

The PNPLA3 gene is linked to the highest risk of NAFLD, according to scientists. The percentage of liver cells that were accumulating fat droplets in children with NAFLD was most closely correlated with a distinct SNP in the gene TM6SF2.

We knew that NAFLD is a genetic disease. Now, thanks to the hundreds of children and families that participated in GOALS, we were able to fill in key details about which genes contribute to having NAFLD and which genes contribute to how severe the disease will be for an individual child.”

Jeffrey Schwimmer, MD, Study Senior Author and Professor, Pediatrics, University of California San Diego School of Medicine

Schwimmer is also a director of the Fatty Liver Clinic at Rady Children’s Hospital-San Diego.

One important factor that determines who may have long-term effects of their liver condition is liver scar tissue (fibrosis). Reduced blood flow throughout the organ as a result of liver fibrosis results in loss of function. If left untreated, it can develop into liver cancer, liver failure, and cirrhosis.

The PARVB rs6006473 SNP was discovered by the researchers to have a novel disease severity connection in children with NAFLD: liver fibrosis. The researchers were able to create a model that might aid in predicting the degree of liver fibrosis in children with NAFLD by integrating this SNP data with that from other genes.

Additionally, children with borderline zone 1 NASH, a form of the illness often identified in children but not adults, had a highly enriched PNPLA3 SNP.

Children with this type of NASH may respond differently to medications, and thus it is worth identifying this genotype in children for clinical trials for NASH.”

 Nidhi Goyal, MD, MPH, Study Lead Author and Assistant Clinical Professor, Pediatrics, University of California San Diego School of Medicine

Goyal is also part of Rady Children’s Hospital-San Diego.

This reinforces that NAFLD in children may be a distinct disease compared to adults. These genetic associations may be pivotal to creating future therapeutics in pediatric NAFLD where currently treatment options are limited.”

Jeffrey Schwimmer, MD, Study Senior Author and Professor, Pediatrics, University of California San Diego School of Medicine

Future therapies may be influenced by the occurrence of unique SNPs in children with NAFLD and how they differ in the way the disease manifests itself.