I148M Patatin-Like Phospholipase Domain-Containing 3 Gene Variant and Severity of Pediatric Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in children. Genetic variability, which is a main player in NAFLD, is especially characterized by polymorphisms in genes involved in the development and progression of the disease to nonalcoholic steatohepatitis (NASH). Recently, the rs738409 C>G adiponutrin/patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism, which encodes the I148M protein variant in the catalytic domain, has been associated with severe steatosis, NASH, and liver fibrosis in adults. In this study, we investigated the association between the rs738409 PNPLA3 gene polymorphism and NAFLD in 149 consecutive children and adolescents (age 5 6-13 years) with biopsy-proven NAFLD. We analyzed the rs738409 polymorphism by a 5 0 -nuclease TaqMan assay and assessed its association with NASH: 41% of the subjects with NAFLD showed heterozygosity and 15% showed homozygosity for the at-risk G allele. The rs738409 genotype did not influence the body mass, adiposity, lipid levels, or insulin resistance and was not associated with alanine aminotransferase levels. Interestingly, the rs738409 G allele was strongly associated with the severity of steatosis (P < 0.0001), the presence of NASH (P < 0.0001), hepatocellular ballooning (P < 0.0001), lobular inflammation (P < 0.0001), and the presence of fibrosis (P 5 0.01) independently of confounders. Individuals carrying two minor G alleles almost always had severe steatosis and NASH, heterozygotes were at intermediate risk, and patients negative for G alleles had milder and often uncomplicated steatosis. Conclusion: The PNPLA3 rs738409 polymorphism is associated with steatosis severity, hepatocellular ballooning, lobular inflammation, and perivenular fibrosis in pediatric NAFLD.

Non-alcoholic Fatty Liver Disease: East Versus West

“…106 Association of G allele with NAFLD is seen in children, adults, obese, non-obese, diabetics, and nondiabetics. 107 Similar association has been reported from Asian countries. 101,108 A recent meta-analysis has confirmed not only the role of this polymorphism in the development of NAFLD across all ethnicities, but also its association with more severe disease with 3.24 times higher risk of high necro-inflammatory scores and liver fibrosis in GG compared with CC genotype.…”

Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents

“…We employed an additive genetic model to test the effect of the PNPLA3 variant (Valenti et al 2010c;Sookoian and Pirola 2011). Given the striking association between PNPLA3 and ultrasonographic severity of steatosis, we kept in the multivariate model variables that were significantly associated with steatosis severity after correction for PNPLA3 I148M.…”

“…To date, it is not known whether specific dietary patterns predispose to NAFLD independently of BMI or whether diet may protect against the development of the NAFLD (Anitha Rani and Sathiyasekaran 2013;Valenti et al 2010a). Excessive consumption of simple sugars has been reported to promote the development of NAFLD in adults.…”

“…The I148M variant influences liver fat without independently of body mass index, dyslipidemia, or insulin resistance, and it has been associated with severe steatosis, NASH, and liver fibrosis (Valenti et al 2002(Valenti et al , 2006(Valenti et al , 2010aMiele et al 2008;Dongiovanni et al 2010), even if severe obesity exposed an association between I148M, insulin resistance, and lower triglycerides in Northern European subjects (Krarup et al 2012;Palmer et al 2012). We previously showed that in overweight children with increased liver enzymes, the PNPLA3 I148M polymorphism is enriched compared to the general population (homozygosity for the 148M risk allele was 16 vs. 5 % in the general population) and represents a non-invasive early marker of NASH and fibrosis (Valenti et al 2010a). …”

Understanding the Role of PNPLA3 Genetic Variants in Patients with Chronic Hepatitis C Infection

“…The PNPLA3 gene encodes a 481 amino acid protein of unknown function that belongs to the patatin-like phospholipase family; the progenitor of this family, patatin, has nonspecific lipid acyl hydrolase activity. Following this breakthrough discovery, several candidate gene studies have demonstrated that the G allele of PNPLA3 single nucleotide polymorphism (SNP) influences liver fat accumulation, is associated with disease severity in adult and pediatric populations with NAFLD, and ultimately increases the risk of NASH [2][3][4][5]. These results did not go unnoticed among colleagues working in the hepatitis C virus (HCV) field, as several studies were designed to assess the clinical role of the PNPLA3 polymorphisms in patients with chronic hepatitis C. The reasons for this interest are many fold.…”