The SNPs under discussion are located in the insulin-response element of the APOC3 Protein Tyrosine Kinase inhibitor gene promoter. In one study, the variant promoter was less responsive to the suppressive effect of insulin.13 Thus,

the variant SNPs may modulate the suppressive effect of insulin on APOC3 expression in states of adequate insulin, but become irrelevant in insulin-resistant states, such as obesity and metabolic syndrome. Further studies on these aspects should help clear the air on discrepant findings on the association of APOC3 variants with NAFLD. PNPLA3, also known as adiponutrin, is a gene located on chrome 22q13 that encodes for a 481-aa protein with triacylglycerol lipase activity, which mediates triacylglycerol hydrolysis. Its expression is mainly on the surface of lipid droplets in hepatocytes and adipocytes, and is regulated by insulin. Two SNPs in this gene have been investigated in relation to NAFLD:

(i) a G-to-C change leading click here to substitution of isoleucine with methionine at codon 148 (I148M; rs738409), and (ii) a G-to-T change leading to substitution of serine with isoleucine at codon 453 (S453I; rs6006460). In contrast to the APOC3 variants, association of PNPLA3 I148M variant with NAFLD is much clearer, with most studies showing an increased risk though the strength of association has varied. In a large genome-wide association the study of subjects included in the Dallas Heart study, the mutant allele was a major determinant of increased MCE公司 hepatic fat content and hepatic inflammation, independent of BMI, diabetes status, ethanol use and ancestry; further, this allele was most common in Hispanics, the subgroup most susceptible to NAFLD.14 In another study from Italy and the UK, this variation was associated with severity of steatosis and liver fibrosis, independent of age, BMI, and diabetes.15 A recent meta-analysis showed that the I148M polymorphism exerts a strong influence not only on liver fat

accumulation (73% higher lipid content with GG genotype than with CC genotype) but also on disease severity at histology (3.24-fold greater risk of high necro-inflammatory scores and 3.2-fold higher risk of liver fibrosis with GG than CC genotype).16 These data clearly indicate that this SNP is a strong modifier of occurrence and natural history of NAFLD irrespective of ethnic origin.16 In fact, even in the study by Petersen et al.5 that showed association of APOC3 variants with NAFLD in Indian men, the presence of GG genotype of PNPLA3 was associated with higher liver triglyceride content. Furthermore, the association of this PNPLA3 variant with NAFLD begins in early childhood, and is present in both obese and non-obese persons, and in those with and without diabetes.17,18 Hence, the finding of Hyysalo et al.10 that Finnish carriers of PNPLA3 GG genotype had a 2.7-fold higher hepatic fat than those with CC genotype is no surprise.