Low-Density Lipoprotein Cholesterol and the Risk of Cancer: A Mendelian Randomization Study
Low-Density Lipoprotein Cholesterol and the Risk of Cancer: A Mendelian Randomization Study
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DOI：
10.1093/jnci/djr008
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发表时间：
2011-03-01
影响因子：
10.3
通讯作者：
Nordestgaard, Borge G.
中科院分区：
文献类型：
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作者：
Benn, Marianne;Tybjaerg-Hansen, Anne;Nordestgaard, Borge G.
低密度脂蛋白（LDL）胆固醇血浆水平低与癌症风险增加有关，但这种关联是否是因果关系尚不清楚，我们研究了10 613名参与者在哥本哈根城市心脏研究（CCHS）和59 566名参与者在哥本哈根一般人群研究，其中6816人已发展为癌症2009年5月。对个体进行PCSK 9 R46 L（rs 11591147）、ABCG 8 D19 H（rs 11887534）、APOE R112 C（rs 429358）和R158 C（rs7412）多态性基因分型，所有这些多态性都与终生血浆LDL胆固醇水平降低相关。在甘油三酯水平低于354 mg/dL的样本中，使用弗里德瓦尔德方程计算血浆LDL胆固醇，并在甘油三酯水平较高的样本中直接通过比色法测量。采用考克斯比例风险回归分析前瞻性估计癌症风险，并采用逻辑回归分析进行横断面估计。使用工具变量分析研究因果关系。所有的统计检验都是双侧的。在CCHS中，与血浆LDL胆固醇水平高于第66百分位数（> 158 mg/dL）相比，低于第10百分位数（< 87 mg/dL）的患者患癌症的风险增加43%（95%置信区间[CI] = 15%至79%）。这些多态性与LDL胆固醇水平降低高达38%（95%CI = 36%至41%）相关，但与癌症风险增加无关。两项研究中所有基因型合并导致血浆LDL胆固醇水平降低50%的癌症因果优势比为0.96（95% CI = 0.87 - 1.05），而CCHS中血浆LDL胆固醇水平降低50%的癌症风险比为1.10（95%CI = 1.01 - 1.21）（因果比值比与观察到的风险比的P = 0.03）。低血浆LDL胆固醇水平与癌症风险增加密切相关，但遗传性LDL胆固醇降低与癌症风险增加无关。这一发现表明低LDL胆固醇水平本身不会导致癌症。
Low plasma levels of low-density lipoprotein (LDL) cholesterol are associated with an increased risk of cancer, but whether this association is causal is unclear.We studied 10 613 participants in the Copenhagen City Heart Study (CCHS) and 59 566 participants in the Copenhagen General Population Study, 6816 of whom had developed cancer by May 2009. Individuals were genotyped for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms, all of which are associated with lifelong reduced plasma LDL cholesterol levels. Plasma LDL cholesterol was calculated using the Friedewald equation in samples in which the triglyceride level was less than 354 mg/dL and measured directly by colorimetry for samples with higher triglyceride levels. Risk of cancer was estimated prospectively using Cox proportional hazards regression analyses and cross-sectionally by logistic regression analyses. Causality was studied using instrumental variable analysis. All statistical tests were two-sided.In the CCHS, compared with plasma LDL cholesterol levels greater than the 66th percentile (> 158 mg/dL), those lower than the 10th percentile (< 87 mg/dL) were associated with a 43% increase (95% confidence interval [CI] = 15% to 79% increase) in the risk of cancer. The polymorphisms were associated with up to a 38% reduction (95% CI = 36% to 41% reduction) in LDL cholesterol levels but not with increased risk of cancer. The causal odds ratio for cancer for a 50% reduction in plasma LDL cholesterol level due to all the genotypes in both studies combined was 0.96 (95% CI = 0.87 to 1.05), whereas the hazard ratio of cancer for a 50% reduction in plasma LDL cholesterol level in the CCHS was 1.10 (95% CI = 1.01 to 1.21) (P for causal odds ratio vs observed hazard ratio = .03).Low plasma LDL cholesterol levels were robustly associated with an increased risk of cancer, but genetically decreased LDL cholesterol was not. This finding suggests that low LDL cholesterol levels per se do not cause cancer.