Page 114 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Vitamin D and breast cancer

and breast cancer risk. Five complementary MR methods, may reflect residual confounding (e.g., sun exposure,
namely IVW, MR-Egger, weighted median, simple mode, physical activity) or subtype-specific effects (e.g., estrogen
and weighted mode, were systematically employed to assess receptor vs. estrogen receptor tumors), warranting
−
+
the robustness of the causal estimates. The primary IVW further investigation. Previous observational studies may
analysis, which offers the most accurate estimate under have been confounded by unmeasured environmental
valid instrumental variable assumptions, produced an OR factors, which in turn affect the accuracy of the results. In
of 1.02 (95% CI: 0.93 – 1.12, p=0.68) for breast cancer risk contrast, the MR method was able to effectively rule out
per unit increase in genetically predicted Vitamin D levels. interfering factors by mimicking randomized controlled
Likewise, the supplementary MR methods consistently trials using genetic variants as instrumental variables, and
showed no associations: MR-Egger (OR: 1.05, 95% CI: 0.85 this study provided clearer evidence that there is no direct
– 1.30, p=0.64), weighted median (OR: 1.01, 95% CI: 0.89 causal relationship between Vitamin D and breast cancer.
– 1.15, p=0.86), simple mode (OR: 1.06, 95% CI: 0.82 – Given the European ancestry of the study population,
1.38, p=0.65), and weighted mode (OR: 1.04, 95% CI: 0.85 these findings may have limited generalizability to other
– 1.28, p=0.70). To deal with potential pleiotropic bias, a ethnic groups, which affects the general applicability of the
formal evaluation of horizontal pleiotropy was carried out conclusions of the study. Although this study did not find
using the MR-Egger intercept test. The intercept term did a causal association between Vitamin D levels and breast
not significantly deviate from zero (intercept = −0.002, cancer in the European population, this does not exclude
p=0.51), indicating that there was no substantial directional the potential role of Vitamin D in the prevention and
pleiotropy affecting the results. Sensitivity analyses further treatment of breast cancer. Considering the interference
strengthened the robustness of these findings. Cochran’s Q and synergistic effects of other potential factors, future
statistic demonstrated no significant heterogeneity across research needs to adopt a more comprehensive and
instrumental variable estimates (Q = 18.3, p=0.25 for multidimensional approach, continuously optimizing and
IVW; Q = 17.9, p=0.27 for MR-Egger), which supported improving research methods to explore the relationship
the suitability of the fixed-effects model. Leave-one-out between Vitamin D and breast cancer more thoroughly.
analyses verified that no SNP disproportionately influenced
the null association, with all iteratively excluded SNP- The occurrence and development of breast cancer is
specific estimates remaining within the null range (ORs: a multifactorial and multistage process, involving the
0.98 – 1.03). In general, these analyses provide strong interaction of various factors such as genetics, environment,
evidence against a causal relationship between Vitamin D and lifestyle. Therefore, when studying the relationship
levels and breast cancer. It is quite interesting to note that between Vitamin D and breast cancer, we need to fully
these findings, while seemingly counterintuitive given the consider the potential interference or synergistic effects
previous assumptions and speculations about the role of that other factors may have. For instance, the interaction
Vitamin D in health, are based on a comprehensive and of Vitamin D with other nutrients, hormones, or lifestyle
methodologically sound approach. This challenges existing factors may influence its role in breast cancer. Moreover, it
hypotheses and opens up new avenues for research. For is worth noting that although the results of this study are
instance, future studies should examine gene-environment based on large-scale genetic data and advanced statistical
interactions (e.g., Vitamin D × ultraviolet exposure) methods, certain limitations still exist. For example,
or nutrient–nutrient interactions (e.g., Vitamin D with sample selection, data quality, assumptions of statistical
calcium intake) that may modulate breast cancer risk. In models, and the racial limitations of this study may impact
addition, investigating whether different sub-populations the research findings. Therefore, we need to interpret
or disease subtypes respond differently to Vitamin D levels these results with caution and continuously optimize
in relation to breast cancer risk could potentially explain and improve methods in future research to enhance the
the null findings in this study at a more granular level. accuracy and reliability of the study.
In future explorations, we recommend adopting a
4. Discussion longitudinal research design to track changes in individuals’
This study did not find a significant causal association Vitamin D levels and their long-term relationship with
between Vitamin D levels and breast cancer. However, as the risk of developing breast cancer. Longitudinal studies
the study population was limited to European populations, can provide time-series data, which helps to reveal the
the applicability of these results to other ethnic groups dynamic relationship between changes in Vitamin D
remains to be further investigated. While our MR analysis levels and breast cancer risk. In addition, consideration
found no genetic evidence for causality, observational can be given to combining genetic information with
associations between Vitamin D and breast cancer individuals’ lifestyles, dietary habits, and environmental

Volume 9 Issue 3 (2025) 106 doi: 10.36922/EJMO025130064