The Causal Effect of Reproductive Factors on Breast Cancer: A Two-Sample Mendelian Randomization Study

Jia, Lijun; Lv, Wei; Liang, Liang; Ma, Yuguang; Ma, Xingcong; Zhang, Shuqun

doi:10.3390/jcm12010347

Cited by 11 publications

(9 citation statements)

References 46 publications

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Section: Discussionsupporting

confidence: 83%

“…Point estimates for the effect of age at last birth across the univariable and multivariable models suggest an adverse effect of a younger age at last birth on ER negative breast cancer risk, which is consistent with a previous MR study, (31) but conflicts with the observational literature. (7,8,(24)(25)(26) It may seem implausible to adjust for ever parous status in the analysis of age at first and last birth on breast cancer risk outcomes since these events only occur in women who have given birth and therefore ever being parous could not observationally confound or mediate this relationship.…”

Section: Discussionsupporting

confidence: 78%

“…MR studies have consistently found little evidence of an effect of age at first birth, (30,31) (OR 0.92; 0.79-1.07 (30) ), (30) but interestingly, some evidence for a protective effect of a later age at last birth on breast cancer risk (OR 0.69; 0.54-0.88), in contrast to observational data. (31) An MR identified an estimate reflecting a higher number of births reduces breast cancer risk although confidence intervals span the null (OR 0.70; 0.44-1.11). (30) It is currently unclear how each reproductive event affects risk in isolation since these traits are highly correlated with, and/or causally linked to other reproductive factors as well as age at menarche and menopause, and adiposity measures, (32,33) which are established breast cancer risk factors.…”

Section: Introductionmentioning

confidence: 94%

“…Mendelian randomisation (MR), a method less likely to be affected by confounding and reverse causation, (28,29) has been used to assess the causal relationship between reproductive factors and breast cancer risk by using genetic variants robustly associated with the exposure as instruments. MR studies have consistently found little evidence of an effect of age at first birth, (30,31) (OR 0.92; 0.79-1.07 (30) ), (30) but interestingly, some evidence for a protective effect of a later age at last birth on breast cancer risk (OR 0.69; 0.54-0.88), in contrast to observational data. (31) An MR identified an estimate reflecting a higher number of births reduces breast cancer risk although confidence intervals span the null (OR 0.70; 0.44-1.11).…”

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

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Evaluating the causal impact of reproductive factors on breast cancer risk: a multivariable mendelian randomization approach

Prince,

Howe,

Sanderson

et al. 2024

Preprint

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Background: Observational evidence proposes a protective effect of having children and an early age at first birth on the development of breast cancer, however the causality of this association remains uncertain. In this study we assess whether these reproductive factors impact breast cancer risk independently of age at menarche, age at menopause, adiposity measures and other reproductive factors that have been identified as being causally related to or genetically correlated with the reproductive factors of interest. Methods: We used genetic data from UK Biobank (273,238 women) for reproductive factors, age at menarche and menopause, and adiposity measures, and the Breast Cancer Association Consortium for risk of overall, estrogen receptor (ER) positive and negative breast cancer as well as breast cancer subtypes. We applied univariable and multivariable Mendelian randomization (MR) to estimate direct effects of ever parous status, ages at first birth and last birth, and number of births on breast cancer risk. Results: We found limited evidence of an effect of age at first birth on overall or ER positive breast cancer risk in either the univariable or multivariable analyses. While the univariable analysis revealed an effect of later age at first birth decreasing ER negative breast cancer risk (Odds ratio (OR): 0.76, 95% confidence interval:0.61-0.95 per standard deviation (SD) increase in age at first birth), this effect attenuated with separate adjustment for age at menarche and menopause (e.g., OR 0.83, 0.62-1.06 per SD increase in age at first birth, adjusted for age at menarche). In addition, we found evidence for an effect of later age at first birth on decreased human epidermal growth factor receptor 2 enriched breast cancer risk but only with adjustment for number of births (OR 0.28 (0.11-0.57) per SD increase in age at first birth). We found little evidence for direct effects of ever parous status, age at last birth or number of births on breast cancer risk, however, analyses of ever parous status and age at last birth were limited by weak instruments in the multivariable analysis. Conclusions: This study found minimal evidence of a protective effect of earlier age at first birth on breast cancer risk, while identifying some evidence for an adverse effect on ER negative breast cancer risk. However, multivariable MR of ever parous status and age at last birth is limited by weak instruments which might be improved in future studies with larger sample sizes and when additional genetic variants related to reproductive factors are identified.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Evaluating the causal impact of reproductive factors on breast cancer risk: a multivariable mendelian randomization approach

Prince,

Howe,

Sanderson

et al. 2024

Preprint

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The causal relationship between ankylosing spondylitis and the risk of ovarian cancer

Ma,

Cui,

Shi

et al. 2023

Human Immunology

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The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study

Zhang,

Li,

Liu

et al. 2024

BMC Women's Health

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Background Pelvic floor dysfunction (PFD) is an extremely widespread urogynecologic disorder, the prevalence of which increases with aging. PFD has severely affected women’s quality of life and has been called a social cancer. While previous studies have identified risk factors such as vaginal delivery and obesity for PFD, other reproductive factors, including age at menarche (AAMA), have been largely overlooked. Therefore, we used a Mendelian randomization (MR) study for the first time to investigate the potential causal relationship between reproductive factors and PFD. Methods We obtained summary statistics from genome-wide association studies (GWAS) for female genital prolapse (FGP), stress urinary incontinence (SUI), and five reproductive factors. Two-sample Mendelian randomization analysis (TSMR) was performed to explore the causal associations between these factors. The causal effects of reproductive factors on FGP and SUI were primarily estimated using the standard inverse variance weighting (IVW) method, with additional complementary and sensitivity analyses conducted using multiple approaches. A multivariate Mendelian randomization (MVMR) study was also conducted to adjust for pleiotropic effects and possible sources of selection bias and to identify independent exposure factors. Results Our findings revealed that advanced age at first sexual intercourse (AFS) and age at first birth (AFB) exhibited negative causal effects on both FGP and SUI. AAMA showed negative causal effects solely on FGP, while age at last live birth (ALB) and age at menopause (AAMO) did not demonstrate any causal effect on either FGP or SUI. And the MVMR results showed that AFB and AFS had independent negative causal effects on FGP and SUI, respectively. Conclusions This study, for the first time, investigates the causal relationship between reproductive factors and PFD. The results suggested a causal relationship between some reproductive factors, such as AFB and AFS, and PFD, but there were significant differences between FGPand SUI. Therefore, future studies should explore the underlying mechanisms and develop preventive measures for reproductive factors to reduce the disease burden of PFD.

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The Causal Effect of Reproductive Factors on Breast Cancer: A Two-Sample Mendelian Randomization Study

Cited by 11 publications

References 46 publications

Evaluating the causal impact of reproductive factors on breast cancer risk: a multivariable mendelian randomization approach

Evaluating the causal impact of reproductive factors on breast cancer risk: a multivariable mendelian randomization approach

The causal relationship between ankylosing spondylitis and the risk of ovarian cancer

The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study

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