Association between age at menarche and cardiovascular disease: A systematic review on risk and potential mechanisms.

Age at menarche (AAM) has been reported to be associated with the risk of cardiovascular disease (CVD), but the shape of and the mechanisms behind this association remain unclear. We reviewed the data on the association between AAM and different subtypes of CVD, and used shared genetic loci to identify possible mechanisms underlying this association using shared genetic association. We searched the databases of PubMed, Web of Science and Embase through to April 2017. We included articles with any clinically manifest CVD endpoint and for any ethnicity. We identified single nucleotide polymorphisms (SNPs) for AAM in genome-wide association studies (GWAS) in Caucasians through PubMed and HuGE Navigator, and searched whether these SNPs or any of their proxies were associated with any CVD-related trait. Eight studies in Caucasian populations reported an inverse linear relation between AAM and CVD risk, whereas one large study reported a significant U-shaped relation between them. Data from Asian populations were contradictory and inconclusive. In total, 122 AAM SNPs were identified at a genome-wide significance level (p<5×10-8). Of those, 18 were also associated with various CVD-related traits, primarily body mass index (BMI), obesity, and height. In conclusion, early AAM and possibly also late AAM increase the risk of CVD in Caucasian populations. Weight and height may be part of the mechanism underlying the relation between AAM and CVD risk in Caucasians. Data on other ethnicities are too limited for meaningful analysis and conclusions.