A conceptual illustration of Fatty liver cells in the shape of a liver

Multiple gene variants, including some previously unknown, have been linked to nonalcoholic fatty liver disease (NAFLD) in children. Researchers confirmed that the PNPLA3 gene is associated with the greatest risk for having NAFLD. A different SNP in the gene TM6SF2 was most strongly associated with what percentage of liver cells was storing fat droplets in children with the condition.

The findings are published in this month’s online issue of Hepatology. The research was led by scientists at University of California San Diego School of Medicine.

In NAFLD, liver cells inappropriately store large droplets of fat, which interfere with the normal functioning of the liver. The condition can progress to liver inflammation and nonalcoholic steatohepatitis (NASH), followed by cirrhosis, and liver cancer.

The American Liver Foundation estimates 10 percent of all children in the US have NAFLD, and because they will have the disease most of their lives, they are at greater risk for complications, such as requiring a liver transplant as young adults. Pediatric NAFLD is also associated with an increased risk of cardiovascular disease, type 2 diabetes, and adult mortality.

Earlier research has identified some individual genomic variations of NAFLD associated with single nucleotide polymorphisms (SNPs) and other markers, such as DNA methylation.

In the current studies, one group assessed genetic risk of transmission of NAFLD by looking at 252 family trios (mother, father and child with biopsy-proven NAFLD). In related work, researchers examined 822 children with biopsy-proven NAFLD to investigate the association of certain SNPs with disease severity.

“We knew that NAFLD is a genetic disease. Now, thanks to the hundreds of children and families that participated in GOALS [Genetics of Obesity Associated Liver Steatosis studies], 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,” said senior author Jeffrey Schwimmer, MD, professor of pediatrics at UC San Diego School of Medicine and director of the Fatty Liver Clinic at Rady Children’s Hospital-San Diego.

Liver scar tissue (fibrosis) is a key determinant of who will suffer long-term consequences of their liver disease. Liver fibrosis results in diminished blood flow throughout the organ, causing loss of function. Untreated, it can progress to cirrhosis, liver failure, and liver cancer.

These researchers found that the PARVB rs6006473 SNP was highly and significantly associated with liver fibrosis, and thus a new disease severity marker in children with NAFLD. By combining this SNP with information from other genes, the investigators were able to develop a model that could help to predict the severity of liver fibrosis in children with NAFLD.

Additionally, the PNPLA3 SNP was significantly enriched in children with borderline zone 1 NASH, a manifestation of disease commonly found in children but not adults. “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,” said lead author Nidhi Goyal, MD, MPH, assistant clinical professor of pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego.

“This reinforces that NAFLD in children may be a distinct disease compared to adults,” Schwimmer said. The presence of novel SNPs in children with NAFLD and how they differentially affect disease outcomes may help guide future treatments. “These genetic associations may be pivotal to creating future therapeutics in pediatric NAFLD where currently treatment options are limited.”

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