Negative Effects of Age at Menarche on Risk of Cardiometabolic Diseases in Adulthood: A Mendelian Randomization Study

被引:19
作者
Cao, Min [1 ]
Cui, Bin [1 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Clin Ctr Endocrine & Metab Dis, Shanghai Inst Endocrine & Metab Dis, Ruijin Hosp,Sch Med, 197 Ruijin Er Lu, Shanghai 200025, Peoples R China
基金
中国国家自然科学基金;
关键词
mendelian randomization; age at menarche; type; 2; diabetes; coronary artery diseases; cardiometabolic traits; GENOME-WIDE ASSOCIATION; CORONARY-HEART; CARDIOVASCULAR-DISEASE; WOMEN; INSTRUMENTS; CANCER; METAANALYSIS; POPULATION; MENOPAUSE; CHILDREN;
D O I
10.1210/clinem/dgz071
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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.
引用
收藏
页码:515 / 522
页数:8
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