血脂遗传评分、HMGCR 基因与癌症风险：一项孟德尔随机化研究。

Blood lipid genetic scores, the HMGCR gene and cancer risk: a Mendelian randomization study.

机构信息

Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.

Program in Medical and Population Genetics, The Broad Institute, Cambridge, MA, USA.

出版信息

Int J Epidemiol. 2018 Apr 1;47(2):495-505. doi: 10.1093/ije/dyx237.

DOI:10.1093/ije/dyx237

PMID:29165714

Abstract

BACKGROUND

It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding.

METHODS

We applied Mendelian randomization analysis to genetic scores, comprising 26-41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26 904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR).

RESULTS

The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80-1.03] unadjusted, and 0.87 (95% CI: 0.78-0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01-1.18) for prostate cancer and 0.89 (95% CI: 0.82-0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder.

CONCLUSIONS

Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers.

摘要

背景

目前尚不清楚血脂、他汀类药物使用与癌症风险之间是否存在因果关系。在某些假设下，使用暴露的遗传标志物进行孟德尔随机分析可以消除反向因果关系和混杂。

方法

我们应用孟德尔随机分析，使用包含 26-41 个单核苷酸多态性（SNP）的遗传评分作为甘油三酯和低、高密度脂蛋白胆固醇（LDLC、HDLC）的工具变量（IV），对 26904 名个体进行前瞻性队列研究，其中有 6607 例新发癌症。我们还研究了他汀类药物治疗靶点羟甲基戊二酰辅酶 A 还原酶（HMGCR）基因中 SNP（rs12916）与癌症风险的关系。我们使用逻辑回归和 SNP 多效性调整分析来估计每个标准差的比值比（OR）。

结果

未经调整的甘油三酯 IV 作为任何癌症预测因子的 OR 为 0.91（95%置信区间（CI）：0.80-1.03），多效性调整分析的 OR 为 0.87（95% CI：0.78-0.95）。对于每降低 1LDLC 一个 T 等位基因的 HMGCR rs12916，OR 分别为前列腺癌 1.09（95% CI：1.01-1.18）和乳腺癌 0.89（95% CI：0.82-0.96）。LDLC IV 与前列腺癌或乳腺癌无关。IVs 与肺癌、结肠癌或膀胱癌之间没有关联。