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Genetic risk factors and disease severity in children with nonalcoholic fatty liver disease

Results of a study on NAFLD in children, including those from a highly affected ethnic population, show that some genetic variants increase risk of disease, particularly its more severe form. NAFLD has become the most common form of chronic liver disease in children. In its early stages, the disease can involve fat accumulation in the liver, followed in some children by inflammation and tissue damage, placing them at risk for more severe outcomes, such as liver cirrhosis and the need for a liver transplant. NAFLD occurs in people of all races and ethnicities, but in the United States the disease is more likely to affect those of Hispanic ethnicity than those from other ethnic groups, such as non-Hispanic Black persons. While it often tracks with other forms of metabolic disease, such as obesity and diabetes, questions remain as to why only some individuals with these metabolic diseases develop NAFLD. Studies with adult participants have shown that genetic variations appear to underlie some of this risk, but evidence in children is more limited.

A group of scientists in the Nonalcoholic Steatohepatitis Clinical Research Network studied more than 800 girls and boys who were diagnosed with NAFLD at varying stages, based on microscopic evaluation of liver biopsies. The majority of the children were of Hispanic ethnicity. Scientists analyzed DNA from blood samples given by the children and their parents to identify genetic variants associated with increased risk for developing NAFLD. Among several genetic variants identified, one in the PNPLA3 gene showed the strongest association with disease. Children who inherited this genetic variant from both parents, the majority of whom were of Hispanic ethnicity, developed more severe disease at a younger age and at a lower level of overweight. The PNPLA3 variant is also linked to NAFLD in people who develop the disease later in life, but in this study, it was found to be associated with patterns of fatty liver disease that are primarily seen only in children, suggesting that this variant can affect the livers of people differently across the lifespan. The researchers further evaluated disease stage of the liver samples against a selection of genetic variants, including the PNPLA3 variant, to pinpoint which were likely to contribute to severe disease. They found some variants were associated with early fat accumulation in the liver, while others occurred in tandem with inflammation and tissue damage.

This study enhances understanding of genetic risk factors for NAFLD and its severity in children, who show some unique features of the disease compared to adults. Because the majority of study participants were of Hispanic ethnicity, these findings are particularly valuable for this at-risk population. Insights from this study can help explain differences in NAFLD risk, disease severity, and treatment response, providing foundational knowledge needed for therapeutic development and improving clinical care for these children.

Goyal NP, Rosenthal SB, Nasamran C, …Schwimmer JB; for the NASH Clinical Research Network. Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children. Hepatology doi:10.1002/hep.32570, 2022.

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