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. 2025 Aug 1;104(31):e43676.
doi: 10.1097/MD.0000000000043676.

Impact of age at first sexual intercourse on the development and prognosis of breast cancer: A two-sample Mendelian randomization study with NHANES validation

Xinghuang Yang  1 , Tianyu Deng  1 , Tianai Xu  1   2 , Min Ma  1   2   3
Affiliations

Impact of age at first sexual intercourse on the development and prognosis of breast cancer: A two-sample Mendelian randomization study with NHANES validation

Xinghuang Yang et al. Medicine (Baltimore). .

Abstract

This study examines the potential link of age at first sexual intercourse (AFS) with breast cancer (BC). A two-sample Mendelian randomization (MR) method was leveraged to examine the possible link of AFS with BC. The causal effect of AFS on BC was primarily appraised by an inverse variance weighted method. Sensitivity analyses were applied to appraise the stability of MR results, involving Cochran Q test, MR-Egger intercept analysis, outlier test (MR-pleiotropy residual sum and outlier), and leave-one-out method. The National Health and Nutrition Examination Survey was leveraged to validate the impact of AFS on BC prognosis. Kaplan-Meier curves, Cox regression analysis, and restricted cubic splines were generated to appraise the link of AFS with BC. The inverse variance weighted exhibited a positive causal effect of AFS on BC (odds ratio = 1.237, 95% confidence interval = 1.077-1.420, P = .003) with reliable and stable results. Nevertheless, other methods revealed no notable association. In addition, none of the above sensitivity analyses revealed any violation of the MR assumptions. The results from the investigated sample cohort of 92,062 women showed that a high AFS was tied to worse outcomes in BC patients (hazard ratio = 1.148, 95% confidence interval = 1.048-1.258, P = .003). This correlation remained consistent across various subgroups. The study suggests that there is a noticeable link between AFS and BC, providing further evidence for predicting the risk and prognosis of BC.

Keywords: Mendelian randomization; NHANES; breast cancer; female reproduction; first sexual intercourse.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Mendelian randomization research design.
Figure 2.
Figure 2.
NHANES data selection flow chart. NHANES = National Health and Nutrition Examination Survey.
Figure 3.
Figure 3.
Scatter plot for the causal association between AFS and BC. AFS = age at first sexual intercourse, BC = breast cancer.
See this image and copyright information in PMC

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