The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life

Background & aims: Childhood obesity is a growing problem worldwide. Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity in children. Recently, the PNPLA3 gene I148M (rs738409) variant was demonstrated to be strongly associated with hepatic steatosis in obese adults. In this study we add further insight into the role of PNPLA3 by exploring whether this association begins early in life in obese children or becomes manifest only in adulthood. Methods: Four hundred and seventy-five obese/overweight children and adolescents were genotyped for the I148M allele. Clinical and biochemical parameters were collected for all participants, including indices of hepatic injury, glucose tolerance and insulin resistance. Ultrasound imaging of the liver was obtained to assess the degree of steatosis in a subset of children. Results: Carriers of two 148M alleles had a 52% increase in circulating ALT levels compared to carriers of two 148I alleles, with individuals with one 148M allele showing a 9.5% increase (p = 0.001). AST concentration was also significantly higher in carriers of two and one M alleles (17.4% and 4%, respectively, p = 0.022). A total of 36% of carries of two 148M alleles showed elevated ALT, defined as >30U/L, compared to only 10% of carriers of two 148I alleles (p <0.001). Liver steatosis was more prevalent in carriers of two 148M alleles. Glucose tolerance and insulin sensitivity were similar across all three genotypes. Conclusions: Our data show that the PNPLA3 gene I148M variant is associated with increased levels of ALT/AST in obese children and adolescents, suggesting that it confers genetic susceptibility to liver damage from a young age.