Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.
Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.
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DOI：
10.1056/nejmoa0907295
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发表时间：
2010-03-25
期刊：
影响因子：
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通讯作者：
Shulman GI
中科院分区：
文献类型：
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作者：
Petersen KF;Dufour S;Hariri A;Nelson-Williams C;Foo JN;Zhang XM;Dziura J;Lifton RP;Shulman GI
非酒精性脂肪肝与肝脏胰岛素抵抗和 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（已知非酒精性脂肪肝患病率较高的群体）中，我们对编码载脂蛋白 C3 (APOC3) 的基因中的两个单核苷酸多态性 (SNP) 进行了基因分型，这两个单核苷酸多态性 (SNP) 已知与高甘油三酯血症相关（rs2854116 [T-455C] 和 rs2854117 [C-482T]）。测量血浆载脂蛋白 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受测试后的血浆甘油三酯浓度和视黄基脂肪酸酯吸收以及血浆甘油三酯清除率。还对 163 名健康非亚裔印度男性的肝脏甘油三酯含量和 APOC3 基因型进行了评估。与野生型纯合子相比，APOC3 变异等位基因（C-482T、T-455C 或两者）携带者的空腹血浆载脂蛋白 C3 浓度增加了 30%。他们的空腹血浆甘油三酯浓度也增加了 60%，口服脂肪耐受性测试后血浆甘油三酯和视黄基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非酒精性脂肪肝患病率为 38%，野生型纯合子中非酒精性脂肪肝患病率为 0%（P<0.001）。患有非酒精性脂肪肝的受试者具有明显的胰岛素抵抗。一项涉及非亚裔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肝之间的关联。 APOC3 中的 C-482T 和 T-455C 多态性与非酒精性脂肪肝和胰岛素抵抗相关。
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 non-alcoholic 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.