Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Lancet. 2010 May 8;375(9726):1634-9. doi: 10.1016/S0140-6736(10)60545-4.
Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.
We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.
The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride.
These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.
British Heart Foundation, UK Medical Research Council, Novartis.
甘油三酯介导的途径是否与冠心病有因果关系尚不确定。我们研究了一种调节甘油三酯浓度的遗传变异，以帮助判断因果关系的可能性。
我们评估了载脂蛋白 A5（APOA5）基因的-1131T>C（rs662799）启动子多态性与甘油三酯浓度、其他几种风险因素以及冠心病风险的关系。我们比较了因遗传引起的甘油三酯浓度升高（20842 例冠心病患者，35206 例对照）与前瞻性研究中记录的等效差异的循环甘油三酯浓度（302430 例无心血管疾病史的参与者；279 万人年的风险中有 12785 例冠心病新发病例）。我们分析了 1795 名无心血管疾病史的人中的-1131T>C，这些人有通过核磁共振光谱法获得的脂蛋白浓度和直径的信息。
-1131T>C 的次要等位基因频率为 8%（95%CI 7-9）。-1131T>C 与几种非脂质风险因素或 LDL 胆固醇无显著相关性，与较低的 HDL 胆固醇中度相关（每个 C 等位基因的平均差异为 3.5%[2.6-4.6]；0.053mmol/L[0.039-0.068]），载脂蛋白 AI 降低 1.3%（0.3-2.3）；0.023g/L[0.005-0.041]）和载脂蛋白 B 升高 3.2%（1.3-5.1）；0.027g/L[0.011-0.043]）。相比之下，遗传的每个 C 等位基因使甘油三酯浓度平均升高 16.0%（95%CI 12.9-18.7）或 0.25mmol/L（0.20-0.29）（p=4.4x10(-24)）。冠心病的比值比为 1.18（95%CI 1.11-1.26；p=2.6x10(-7)）每 C 等位基因，这与前瞻性研究中记录的每 16%甘油三酯升高导致的 1.10（95%CI 1.08-1.12）的风险比一致。-1131T>C 与较高的 VLDL 颗粒浓度显著相关（每个 C 等位基因的平均差异为 12.2nmol/L[95%CI 7.7-16.7]；p=9.3x10(-8)）和较小的 HDL 颗粒大小（0.14nm[0.08-0.20]；p=7.0x10(-5)），这些因素可能介导甘油三酯的作用。
这些数据与甘油三酯介导的途径与冠心病之间存在因果关系一致。
英国心脏基金会、英国医学研究理事会、诺华公司。
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