Genetically predicted circulating concentrations of micronutrients and risk of breast cancer: A Mendelian randomization study

Abstract

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B₆ , vitamin B₁₂ and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10^-7 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10^-6 ) higher risk of overall and ER^+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER^-ve breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.

Keywords: Mendelian randomization; breast cancer; causal inference; diet; nutrition.

Figure1.. Forest plot showing results from the Mendelian randomization study to evaluate potential causal associations between 11 nutrients and breast cancer both overall and by estrogen receptor status.

The odds ratios (OR) were calculated using the inverse variance weighted (IVW) method and correspond to a 1-SD increase in the concentration of the nutrients.