ANGPTL4 变异体 E40K 和 T266M 与来自 Look AHEAD 临床试验的非西班牙裔白种美国人的空腹甘油三酯水平降低相关。
ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial.
机构信息
Division of Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and UCL Medical School, London, UK.
出版信息
BMC Med Genet. 2011 Jun 29;12:89. doi: 10.1186/1471-2350-12-89.
BACKGROUND
Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the ANGPTL4 coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D.
METHODS
The association of ANGPTL4 E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels.
RESULTS
Among non-Hispanic White Look AHEAD participants, ANGPTL4 K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels.
CONCLUSIONS
This is the first study to demonstrate that the ANGPTL4 E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that ANGPTL4 genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.
背景
甘油三酯水平升高是心血管疾病的一个危险因素。血管生成素样蛋白 4（Angptl4）是一种代谢因子，通过抑制脂蛋白脂肪酶（LPL）来升高血浆甘油三酯水平。在非糖尿病个体中，ANGPTL4 编码变异 E40K 与较低的血浆甘油三酯水平相关，而 T266M 变异与甘油三酯代谢的影响更为温和。本研究的目的是确定 ANGPTL4 E40K 和 T266M 是否与肥胖和 2 型糖尿病患者的甘油三酯水平相关，以及这些遗传变异对甘油三酯水平的影响是否会因旨在治疗 2 型糖尿病的生活方式干预而改变。
方法
在来自 LOOK AHEAD 临床试验的 2601 名 2 型糖尿病且超重的参与者中，研究了 ANGPTL4 E40K 和 T266M 与空腹甘油三酯水平的关联。此外，我们还检测了基因型与治疗对甘油三酯水平影响之间的相互作用。
结果
在非西班牙裔白人 LOOK AHEAD 参与者中，ANGPTL4 K40 携带者的甘油三酯水平为 1.61±0.62mmol/L，比 E40 纯合子低 0.33mmol/L（p=0.001）。M266 等位基因（MAF 为 30%）纯合子的个体甘油三酯水平为 1.75±0.58mmol/L，比 T266 纯合子低 0.24mmol/L（p=0.002）。即使在从分析中去除 K40 携带者后，M266 与甘油三酯的关联仍然显著（p=0.002）。基因型与体重减轻干预之间没有相互作用对甘油三酯水平的影响。
结论
这是第一项表明 ANGPTL4 E40K 和 T266M 变体与 2 型糖尿病患者较低的甘油三酯水平相关的研究。此外，我们的研究结果表明，ANGPTL4 基因型状态不会改变 LOOK AHEAD 研究中生活方式干预对甘油三酯的反应。
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