Age at menarche and ischemic heart disease: An update mendelian randomization study

Jing Chen; Heng Chen; Qiaozhen Zhu; Qiannan Liu; Yan Zhou; Lan Li; Yan Wang

doi:10.3389/fgene.2022.942861

Age at menarche and ischemic heart disease: An update mendelian randomization study

Front Genet. 2022 Nov 3:13:942861. doi: 10.3389/fgene.2022.942861. eCollection 2022.

Authors

Jing Chen¹, Heng Chen², Qiaozhen Zhu³, Qiannan Liu¹, Yan Zhou¹, Lan Li^{1

4}, Yan Wang⁴

Affiliations

¹ The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
² Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
³ Clinical Medical School, Henan University, Kaifeng, China.
⁴ Department of Pediatrics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Abstract

Background: Although earlier menarche age has been associated with ischemic heart disease in previous observational studies, the relationship's causation has not been shown. Through two-sample Mendelian randomization (MR), we were able to define the causal connection. Methods: We performed Mendelian Randomization (MR) analysis to explore the associations between genetically predicted AAM and IHD. Summary-level databases for exposure and outcome were selected from the MR-Base database (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) connected to AAM at genome-wide significance level (p < 5 × 10^-8) were considered as instrumental variables (IVs). We used four methods to pool MR estimates, including fixed-effects inverse variance weighting (fe-IVW), multiplicative random-effects inverse variance weighting (mre-IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses were performed to evaluate the robustness of the results. PhenoScanner searches and Multivariable Mendelian randomization (MVMR) analysis was used for assessing confounders. Results: 117 SNPs significantly correlated with AAM were screened as instruments, the results of three main methods showed that genetically earlier AAM may have a causal effect on the higher risk of IHD (fe-IVW: OR = 0.80, 95% CI: 0.72-0.88, p < 0.001; mre-IVW: OR = 0.80, 95% CI: 0.70-0.90, p < 0.001; WE: OR = 0.79, 95% CI: 0.66-0.93, p = 0.006). These results were consistent across sensitivity analyses. MR analysis revealed that there was still a relationship between AAM and IHD even when pleiotropic SNPs of confounders were removed employing PhenoScanner searches. In MVMR, the significant association remained after adjusting for biological sex, but it was attenuated with adjustment of body mass index including childhood and adult. Conclusion: Our MR analysis revealed a substantial genetically determined confounder-mediated relationship between an increase in genetically predicted AAM and a lower risk of IHD. By addressing the intervention of body mass index, the risk of IHD may be lowered.

Keywords: age at menarche; causality; ischemic heart disease; mendelian randomization; single nucleotide polymorphisms.