Negative Effects of Age at Menarche on Risk of Cardiometabolic Diseases in Adulthood: A Mendelian Randomization Study
Negative Effects of Age at Menarche on Risk of Cardiometabolic Diseases in Adulthood: A Mendelian Randomization Study
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初潮年龄对成年后心血管代谢疾病风险的负面影响：孟德尔随机研究
DOI：
10.1210/clinem/dgz071
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发表时间：
2020-02-01
影响因子：
5.8
通讯作者：
Cui, Bin
中科院分区：
文献类型：
--
作者：
Cao, Min;Cui, Bin
内容：观察性研究表明，月经初潮早期与心脏代谢疾病有关，但混杂因素使其难以推断因果关系。目的：我们使用孟德尔随机化（MR）来检查月经初潮年龄（AAM）是否与2型糖尿病（T2 D）、冠状动脉疾病（CAD）和心脏代谢特征有因果关系。设计和方法：使用糖尿病遗传学复制和荟萃分析（DIAGRAM）联盟的全基因组关联研究（GWAS）汇总统计量进行双样本MR分析（n = 159 208）T2 D和冠状动脉疾病全基因组复制和荟萃分析加冠状动脉疾病遗传学（CARDIOGRAMplusC 4D）联盟（n = 184 305）用于CAD。我们使用了从已发表的GWAS荟萃分析中提取的122个工具变量（IV），纳入了182 416名女性，以确定AAM对心脏代谢疾病的因果影响，将儿童和成人体重指数（BMI）作为混杂因素。结果：采用MR方法，我们发现AAM晚与CAD风险降低相关（OR，0.92 [95% CI，0.88-0.96]; P = 2.06 x 10（-4）），以及较低的血液水平的对数空腹胰岛素，对数稳态模型评估的胰岛素抵抗（HOMA-IR），β细胞功能（HOMA-B）、甘油三酯和舒张压的对数HOMA，但高密度脂蛋白的血液水平较高。然而，排除BMI相关变异后，相关性大幅减弱。结论：AAM与T2 D之间的因果关系在流行病学研究中观察到的相关性可能主要是通过过度肥胖介导的，因此AAM与T2 D之间的因果关系并不明显。我们建议肥胖可能是未来干预策略的主要目标。
Context: Observational studies have demonstrated that early menarche is associated with cardiometabolic diseases, but confounding factors make it difficult to infer causality.Objective: We used Mendelian randomization (MR) to examine whether age at menarche (AAM) is causally associated with type 2 diabetes (T2D), coronary artery disease (CAD) and cardiometabolic traits.Design and Methods: A 2-sample MR analysis was conducted using genome-wide association study (GWAS) summary statistics from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium (n = 159 208) for T2D and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) consortium (n = 184 305) for CAD. We used 122 instrumental variables (IVs) extracted from a published GWAS meta-analysis incorporating 182 416 women to determine the causal effect of AAM on cardiometabolic diseases, treating childhood and adult body mass index (BMI) as the confounders. Sensitivity analyses were also performed to detect the pleiotropy of the IVs.Results: Employing the MR approach, we found that later AAM was associated with decreased risk of CAD (OR, 0.92 [95% CI, 0.88-0.96]; P = 2.06 x 10(-4)) in adults, as well as lower blood levels of log fasting insulin, log homeostatic model assessment of insulin resistance (HOMA-IR), log HOMA of beta-cell function (HOMA-B), triglycerides, and diastolic blood pressure, but higher blood level of high-density lipoprotein. However, the associations were substantially attenuated after excluding BMI-related variants. MR analyses provide little evidence on the causal effect between AAM and T2D.Conclusions: Our findings showed that AAM did not appear to have a causal effect on the risk of cardiometabolic diseases in adult life, as their associations observed in epidemiological studies might be largely mediated through excessive adiposity. We propose adiposity might be a primary target in future intervention strategy.