The I148M Variant of PNPLA3 Reduces the Response to Docosahexaenoic Acid in Children with Non-Alcoholic Fatty Liver Disease

Abstract

The aim of this secondary analysis of a randomized controlled trial was to test whether the I148M variant of Patatin-like phospholipase domain-containing protein-3 (PNPLA3) is associated with the response to docosahexaenoic acid (DHA) in children with non-alcoholic fatty liver disease (NAFLD). Sixty children with NAFLD were randomized in equal numbers to DHA 250 mg/day, DHA 500 mg/day or placebo. Coherently with the primary analysis, the probability of more severe steatosis after 24 months of DHA supplementation was 50% lower [95% confidence interval (CI) -59% to -42%)] in the combined DHA 250 and 500 mg/day groups versus placebo. The present secondary analysis revealed an independent effect of PNPLA3 status on the response to DHA. In fact, the probability of more severe steatosis was higher (37%, 95% CI 26-48%) for the PNPLA3 M/M versus I/M genotype and lower (-12%, 95% CI -21% to -3%) for the I/I versus I/M genotype (Somers' D for repeated measures). We conclude that the 148M allele of PNPLA3 is associated with lower response, and the 148I allele with greater response, to DHA supplementation in children with NAFLD.

Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial

“…Thus, it is possible that the lack of response to DHA+EPA treatment in decreasing liver fat % in subjects with PNPLA3 I148 MM could be due to the fact that these subjects already have low levels of de novo lipogenesis. That said, it is not known whether PNPLA3 (I148M) GG genotype affects the incorporation of DHA (or EPA) into the liver lipid droplet, although recent evidence in a small study in children suggests that the PNPLA3 (I148M) GG genotype attenuates the benefit of DHA to decrease liver fat (40). These data in children are in agreement with, and are extended by, our data, showing PNPLA3 (I148M) GG genotype is associated with lower levels of DHA enrichment.…”

A “systems medicine” approach to the study of non-alcoholic fatty liver disease

“…The PNPLA3-I148M variant hampers triglyceride esterase causing reduced remodelling of lipid droplets in association with excessive intake of carbohydrates or saturated fatty acids and other genetic factors [60][61][62][63]. The association between the I148M variant and NAFLD holds true both in adults and in adolescents [64][65][66][67][68]; I148M allele homozygosity predisposes to NASH and hepatic fibrosis [56][57][58]. The association between the I148M variant and fibrosis is also evident in chronic viral hepatitis and genetic diseases, such as hereditary haemochromatosis [69][70][71].…”

“…Therefore, both PNPLA3-I148M and TM6SF2E167K may be useful in identifying NAFLD patients at a higher risk of hepatic than cardiovascular complications and the PNPLA3-based categorisation of NAFLD may have therapeutic implications. Preliminary data suggest that I148M-homozygous subjects might benefit from weight loss after a short-term low-carbohydrate diet [68,78]; however, disease progression is modulated by multiple environmental and genetic factors [48,[79][80][81][82]. Thus, PNPLA3 I148M and TM6SF2 variants plus/minus a family history for cirrhosis and/or HCC and ethnicity can be used to stratify patients at risk in clinical practice ( Table 2).…”

Data Uncertainty in Virtual Network Embedding: Robust Optimization and Protection Levels

“…Furthermore, the pathogenesis of NAFLD, and perhaps the response to treatment, is also influenced by different genetic and epigenetic factors, and these factors may profoundly influence the efficacy of specific treatments (129). In support of this assertion, that is supported by the data discussed earlier from adults with NAFLD in the WELCOME study (110), Nobili et al (130) found that in children with NAFLD, the presence of the PNPLA3 I148M gene polymorphism, may reduce the efficacy of DHA on fatty liver.…”