A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents

Abstract

The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04).

Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size.

Fig. 1

Association between PNPLA3 rs738409 SNP and hepatic fat content (hepatic fat fraction [%HFF]) in Caucasians, African Americans, and Hispanics. The %HFF is expressed using box plots; dark blue indicates CC carriers and light blue the CG/GG carriers. P values are adjusted for age, sex, and BMI z-score. Data are shown as median and 95% CI. *P < 0.001; **P = 0.009.

Fig. 2

Hepatic fat content (%HFF)(top left) and insulin sensitivity (glucose disposal rate)(top right) by genotype. Basal, low dose, and high dose insulin dose clamp hepatic glucose production rates (bottom left) and glycerol turnover rates (bottom right) by genotype are expressed using box plots; dark blue indicates CC carriers and light blue the CG/GG carriers. Data are shown as median and 95% CI. *P = 0.04. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Fig. 3

Shown are (A) adipose cell size, as amount of small cells in percentage and (B) adipocyte median in micrometers, by genotype (dark blue indicates CC homozygous and light blue the G carriers). Box plots in (C) illustrate the difference in gene expression of PNPLA3, PNPLA2, SREBP1c, ACACA, PPARγ2, LEP, and SIRT1 by genotype (dark blue indicates CC homozygous and light blue the G carriers). Data are shown as median and 95% CI (*P = 0.005; **P = 0.05; ◆P = 0.03; ◆◆P = 0.04). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]