Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark.
Int J Epidemiol. 2017 Dec 1;46(6):1777-1785. doi: 10.1093/ije/dyx096.
Results from randomized controlled trials (RCTs) have raised concern that the cholesterol-lowering drug ezetimibe might increase the risk of cancer. We tested the hypothesis that genetic variation in NPC1L1, mimicking treatment with ezetimibe, was associated with an increased risk of cancer.
We included 67 257 individuals from the general population. Of these, 8333 developed cancer and 2057 died of cancer from 1968 to 2011. To mimic the effect of ezetimibe, we calculated weighted allele scores based on the low-density lipoprotein (LDL) cholesterol-lowering(= NPC1L1-inhibitory) effect of each variant. We tested the associations of the NPC1L1 allele scores with LDL cholesterol and with risk of any cancer, death from any cancer and 27 site-specific cancers. As a positive control, we tested the association of the NPC1L1 allele scores with risk of ischaemic vascular disease (IVD).
The NPC1L1 allele scores did not associate with risk of any cancer, death from any cancer or with any of 27 site-specific cancers. Hazard ratios (HRs) for a 1-unit increase in internally weighted allele scores were 1.00 (95% confidence interval: 0.98-1.02) for any cancer, and 1.02 (0.98-1.06) for cancer death. The corresponding HR for IVD was 0.97 (0.94-0.99). Results were similar for an externally weighted allele score and for a simple allele count. Finally, the null association with cancer was robust in sensitivity analyses.
Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer. These results suggest that long-term treatment with ezetimibe is unlikely to increase the risk of cancer, in agreement with the overall evidence from ezetimibe RCTs.
随机对照试验（RCT）的结果引起了人们的担忧，即降胆固醇药物依折麦布可能会增加癌症风险。我们检验了这样一个假设，即 NPC1L1 的基因变异，模拟依折麦布的治疗效果，与癌症风险的增加有关。
我们纳入了来自普通人群的 67257 名个体。其中，8333 人在 1968 年至 2011 年间患癌症，2057 人死于癌症。为了模拟依折麦布的效果，我们根据每个变异对低密度脂蛋白（LDL）胆固醇的降低（= NPC1L1 抑制）效果计算了加权等位基因分数。我们检测了 NPC1L1 等位基因分数与 LDL 胆固醇的关联，以及任何癌症的风险、任何癌症的死亡风险和 27 个特定部位癌症的风险。作为阳性对照，我们检测了 NPC1L1 等位基因分数与缺血性血管疾病（IVD）风险的关联。
NPC1L1 等位基因分数与任何癌症的风险、任何癌症的死亡风险或 27 个特定部位癌症的风险均无关联。内部加权等位基因分数每增加 1 个单位的风险比（HR）为 1.00（95%置信区间：0.98-1.02），任何癌症的 HR 为 1.02（0.98-1.06），癌症死亡的 HR 为 0.97（0.94-0.99）。IVD 的相应 HR 为 0.97（0.94-0.99）。对于外部加权等位基因分数和简单的等位基因计数，结果相似。最后，在敏感性分析中，癌症的零关联结果是稳健的。
终生遗传抑制 NPC1L1，模拟依折麦布的治疗效果，与癌症风险无关。这些结果表明，依折麦布的长期治疗不太可能增加癌症风险，这与依折麦布 RCT 的总体证据一致。
