探索端粒长度与冠心病之间因果关系的途径：基于网络的孟德尔随机化研究。
Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.
机构信息
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Y.Z., I.K.K., R.K., A.T., N.L.P., S.H.); and Department of Psychology, University of California, Riverside (C.A.R.).
出版信息
Circ Res. 2017 Jul 21;121(3):214-219. doi: 10.1161/CIRCRESAHA.116.310517. Epub 2017 May 17.
RATIONALE
Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention.
OBJECTIVE
To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design.
METHODS AND RESULTS
Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; =0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; =0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; =0.04).
CONCLUSIONS
Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.
背景
观察性研究发现，白细胞端粒长度（TL）较短是冠心病（CHD）的危险因素，最近有研究提示这种关联可能具有因果关系。然而，TL 与 CHD 的常见代谢危险因素之间的关系尚不清楚。这些危险因素是否可以解释 TL 与 CHD 之间的因果关系，这值得进一步关注。
目的
利用基于网络的孟德尔随机化设计，研究 CHD 的代谢危险因素是否可以调节 TL 较短与 CHD 风险增加之间的因果途径。
方法和结果
采用两样本孟德尔随机化研究设计，使用来自多个全基因组关联研究的汇总统计数据。采用网络孟德尔随机化分析（一种使用遗传变异作为暴露和中介物的工具变量，以推断因果关系的方法）来研究端粒与 CHD 和代谢危险因素之间的因果关系。采用 ENGAGE 端粒联盟的汇总统计数据（n=37684）作为 TL 遗传工具，CARDIoGRAMplusC4D 联盟的数据（病例=22233，对照=64762）用于 CHD，其他联盟的数据用于代谢特征（空腹胰岛素、甘油三酯、总胆固醇、低密度脂蛋白胆固醇、空腹血糖、糖尿病、糖化血红蛋白、体重指数、腰围和腰臀比）。遗传决定的 TL 每增加一个单位，与空腹胰岛素的对数转换值降低 0.07（95%置信区间，-0.01 至 -0.12；=0.01）相关，CHD 的患病风险降低 21%（95%置信区间，3-35；=0.02）。遗传决定的空腹胰岛素水平较高与 CHD 风险增加相关（比值比，1.86；95%置信区间，1.01-3.41；=0.04）。
结论
总体而言，我们的研究结果支持胰岛素作为较短端粒与 CHD 发病机制之间因果关系的中介的作用。
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