Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
N Engl J Med. 2010 Mar 25;362(12):1082-9. doi: 10.1056/NEJMoa0907295.
Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown.
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.
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.
The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.
非酒精性脂肪性肝病与肝胰岛素抵抗和 2 型糖尿病有关。这种关联是否具有遗传基础尚不清楚。
在 95 名健康的亚洲印度男性中，该组人群患有非酒精性脂肪性肝病的患病率很高，我们对载脂蛋白 C3（APOC3）基因中的两个单核苷酸多态性（SNP）进行了基因分型，这两个 SNP 与高甘油三酯血症有关（rs2854116[T-455C]和 rs2854117[C-482T]）。测量了血浆载脂蛋白 C3 浓度、胰岛素敏感性和肝甘油三酯含量。我们还测量了口服和静脉脂肪耐量试验后血浆甘油三酯浓度和视黄醇脂肪酸酯吸收以及血浆甘油三酯清除率。还评估了一组 163 名健康非亚洲印度男性的肝甘油三酯含量和 APOC3 基因型。
APOC3 变异等位基因（C-482T、T-455C 或两者）携带者空腹血浆载脂蛋白 C3 浓度增加 30%，与野生型纯合子相比。他们的空腹血浆甘油三酯浓度也增加了 60%，口服脂肪耐量试验后血浆甘油三酯和视黄醇脂肪酸酯浓度增加了约两倍，血浆甘油三酯清除率降低了 46%。变异等位基因携带者中非酒精性脂肪性肝病的患病率为 38%，而野生型纯合子的患病率为 0%（P<0.001）。患有非酒精性脂肪性肝病的患者存在明显的胰岛素抵抗。一项涉及非亚洲印度男性的验证研究证实了 APOC3 变异等位基因与非酒精性脂肪性肝病之间的关联。
APOC3 中的 C-482T 和 T-455C 多态性与非酒精性脂肪性肝病和胰岛素抵抗有关。
