Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease

Abstract

Background: Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown.

Methods: In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men.

Results: Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease.

Conclusions: The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.

Figure 1. Scattergrams of Liver Triglyceride Content in Asian Indian and Non–Asian Indian Men

Carriers of APOC3 variant alleles (C-482T, T-455C, or both) were compared with APOC3 wild-type homozygotes (C-482 and T-455) in terms of liver triglyceride content. Results are shown for two groups of Asian Indian men (Panel A) and for two groups of non–Asian Indian men (Panel B). The boxes delineate subjects who had nonalcoholic fatty liver disease (hepatic lipid content >5.5%), all of whom were carriers of the variant allele.

Figure 2. Plasma Triglyceride and Retinyl Fatty Acid Ester Concentrations after an Oral Fat-Tolerance Test in Asian Indian Men

Panel A shows the area under the curve (AUC) for plasma triglyceride concentrations after an oral fat-tolerance test in 28 carriers of APOC3 variant alleles (C-482T, T-455C, or both) as compared with 10 APOC3 wild-type homozygotes. Panel B shows the AUC for plasma retinyl ester concentrations in the two groups. Data are means ±SE.

Figure 3. Relative Plasma Triglyceride Concentrations after an Intravenous Fat-Tolerance Test in Asian Indian Men

The relative plasma triglyceride concentrations are shown for 15 carriers of APOC3 variant alleles and 4 wild-type homozygotes. (Relative refers to the fact that starting plasma triglyceride levels were normalized to 100% for each subject.) The area under the curve was significantly higher for the variant-allele carriers (P = 0.046). Data are means ±SE.