The common gene variant of the lysophosphatidic acyltransferase PNPLA3 is associated with subclinical liver injury in young children
Aims: The common adiponutrin (PNPLA3) variant p.I148 M is a risk factor for severe forms of fatty liver disease (NAFLD).1 Recently we have demonstrated that it associated with increased liver stiffness in patients with chronic liver diseases in general.2 Here we analyse the effects of the adiponutrin polymorphism on liver status in a unique cohort of paediatric patients without clinically apparent chronic liver disease.
Methods: In total, we recruited 142 children (100 Caucasians, 42 Asians, age range 5 – 9 years, 64 boys, mean standard deviation score (SDS)-BMI = 1.45). NAFLD was assessed by abdominal ultrasound. The presence of chronic liver diseases was excluded. The PNPLA3 variant was genotyped with PCR-based 5′-nuclease and fluorescence detection (TaqMan) assays.
Results: All children could be genotyped successfully, and the following PNPLA3 genotype frequencies were observed: [II]= 75 (52.8%), [IM]= 57 (40.1%), [MM]= 10 (7.1%). Overall, there was no association between the PNPLA3 genotype and presence of fatty liver (N = 15, Armitage's trend test P > 0.05). However, we detected a significant difference in serum ALT levels between carriers of distinct PNPLA3 genotypes (non-parametric ANOVA P = 0.021). In particular, homozygous risk allele carriers presented with significantly (P = 0.009) higher ALT activities (median 27 IU/L, range 17 – 40 IU/L) at inclusion in the study as compared to carriers of the protective genotype [II] (median 19 IU/L, range 10 – 60 IU/L). In univariate linear regression analysis, both PNPLA3 polymorphism and SDS-BMI were associated with ALT levels (P = 0.049 and P < 0.001, respectively). In the multivariate model, we detected a significant association with the SDS-BMI (P < 0.001) and a trend for the PNPLA3 variant (P = 0.06). Other liver enzymes were not associated with adiponutrin genotypes.
Conclusions: This study in a paediatric cohort encompassing very young children indicates that the PNPLA3 variant p. 148 M is associated with early subclinical liver phenotypes. This points to a screening strategy to detect individuals who – already at a young age – are at risk for PNPLA3-associated steatohepatitis.
 Valenti et al. Hepatology 2012
 Krawczyk et al. J Hepatol 2011
Supported by BMBF grant FKZ 0315084 and DFG LA997.