New research found the genetic variant Patatin-like phospholipase
domain containing protein-3 (PNPLA3) acting in conjunction with the glucokinase
regulatory protein (GCKR) is associated with increased
susceptibility to fatty liver disease in obese children. The study,
published in the March issue of Hepatology,
a journal of the American Association for the Study of Liver Diseases,
determined the PNPLA3 and GCKR single nucleotide polymorphisms (SNPs)
were responsible for up to 39% of the hepatic fat content in this
pediatric population.
Obesity is a global health concern and children are not unscathed by
this epidemic. As a result, experts say nonalcoholic fatty liver disease
(NAFLD) is now the leading cause of chronic liver disease in children
and adolescents in industrialized countries. Previous studies indicate
genetics significantly impacts the susceptibility of developing fatty
liver and nonalcoholic steatohepatitis (NASH), particularly in
early-onset disease, which places greater interest on childhood obesity.
For the current study, a team led by Dr. Nicola Santoro from Yale
University School of Medicine in New Haven, Connecticut recruited 455
obese children and adolescents who underwent genotyping and fasting
triglycerides and lipoprotein particles testing. Participants in this
pediatric cohort had a mean age of 13 years with 181 Caucasian, 139
African American and 135 Hispanic children. Researchers measured hepatic
fat content (HFF%) using magnetic resonance imaging (MRI) in a subset of
142 children.
Study findings show that rs1260326 in the GCKR gene is associated
with higher triglycerides levels and higher levels of very-low-density
lipoproteins (VLDL) in Caucasian and African American children. The GCKR
SNP was associated with fatty liver in each of the three ethnic
groups. A joint effect between PNPLA3 and GCKR SNPs was
responsible for 32% of the HFF% in Caucasian, 39% in African American
and 15% of Hispanic children. “Our findings confirm that obese youths
with genetic variants in the GCKR and PNPLA3 genes may be
more susceptible to fatty liver disease. We need to be cautious, though,
and refrain to automatically extend this observation to the overall
population. In fact, our data refer to a population of obese children
and adolescents. I think that further studies involving lean subjects
and adults may help to further define in more details these
associations,” said Dr. Santoro.
In a related editorial, Valerio Nobili with “Bambino Gesu” Children’s
Hospital and Research Institute in Italy concurs, “Dr. Santoro and
colleagues determined the additive effect of PNPLA3 and GCKR
variants explained over one third of hepatic fat content variance in
obese children." He recommends that ethnicity data be replicated in
larger study cohorts due to the small number of participants in each of
the three groups.
The study authors suggest that the GCKR variant may lead to
accumulation of fat in the liver through an increase in hepatic
triglyceride production and further research is warranted to confirm
their results. Dr. Santoro concludes, “While the small sample size
raises the possibility of false negative results in our study, the
presence of both GCKR and PNLPA3 genetic variants acting
in combination confers susceptibility to fatty liver disease in obese
children.”
