Department of Epidemiology and Biostatistics, School of Public Health Imperial College London London United Kingdom.
Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR) Singapore.
J Am Heart Assoc. 2024 Jul 16;13(14):e032192. doi: 10.1161/JAHA.123.032192. Epub 2024 Jul 9.
Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima-media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship.
We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM-cIMT association to gauge cross-trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high-density lipoprotein, low-density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%-26.6%]). Our cluster-specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP.
We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.
初潮年龄（AAM）与颈动脉内膜中层厚度（cIMT）升高相关，后者是亚临床血管疾病的一个指标，尽管这种关联的机制仍不清楚。更好地了解 AAM 与可改变的心血管代谢危险因素和亚临床动脉粥样硬化之间的关系，可能有助于改善一级预防和心血管疾病的治疗。我们旨在研究 AAM 对 cIMT 的潜在因果作用，并确定和量化这种关系中潜在的心血管代谢危险因素的中介作用。
我们进行了连锁不平衡评分回归分析，将我们感兴趣的暴露因素 AAM、我们感兴趣的结局因素 cIMT 以及 AAM-cIMT 关联的潜在中介因素联系起来，以评估跨性状遗传重叠。我们将可改变的人体测量危险因素（体重指数、收缩压、血脂特征[总胆固醇、甘油三酯、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇]和血糖特征[空腹血糖]）视为潜在的中介因素。然后，我们利用孟德尔随机化的范例来推断 AAM 和 cIMT 之间的因果关系，并确定心血管代谢危险因素是否作为这种效应的潜在中介因素。我们的分析表明，遗传预测的 AAM 与 cIMT、体重指数、收缩压和甘油三酯呈负相关，与高密度脂蛋白、低密度脂蛋白和总胆固醇呈正相关。我们表明，遗传预测的 AAM 对 cIMT 的影响可能部分通过体重指数（20.1%[95%CI，1.4%-38.9%]）和收缩压（13.5%[95%CI，0.5%-26.6%]）介导。我们的聚类特异性孟德尔随机化显示，初潮年龄对体重指数和收缩压的因果效应估计存在异质性。
我们强调了 AAM 与 cIMT 之间潜在因果关系的支持性证据，AAM 对 cIMT 的影响约有三分之一可能通过体重指数和收缩压介导。旨在降低体重指数和高血压的早期干预可能有益于降低因初潮年龄较早而导致的亚临床动脉粥样硬化风险。
