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Strengths of our analysis include a large sample of black and white men, inclusion of dietary and blood magnesium and calcium levels, and analysis of self-reported race with a genetic African ancestry score. Our controls included men without prostate cancer as determined by pros-tate biopsy. We considered using a general clinical population as a control group, however these patients will have a diﬀerent comorbidity profile, may harbor latent prostate cancer leading to a null bias, and may diﬀer with regard to healthcare access or screening. We found no correlation between magnesium or calcium with PSA levels, suggesting our analysis is unlikely to be biased due to any eﬀect of magnesium or calcium on lowering PSA levels used to screen men for prostate cancer. Evaluation of blood markers of magnesium or calcium avoids dietary assessment errors inherent in estimates of dietary intake from food frequency questionnaires. Our single blood magnesium level would thus represent the balance of intake, Coelenterazine from the colon and kidney, and excretion. Blood magnesium levels would not address bone and muscle magnesium stores that may serve as a reserve in times of magnesium deficiency, other hormones (e.g., PTH) known to aﬀect magnesium absorption, or variation attributable to genetic variants in TRMP6 or other proteins responsible for transporting magnesium through the cell. There are technical and financial challenges to
analyzing magnesium within specific cellular or tissue compartments. Interestingly, use of a reported dietary intake estimate suggested the Ca/Mg ratio was linked with prostate cancer risk, while results were weaker using the blood biomarker, perhaps suggesting that dietary intake estimates provide a more stable estimate of sustained calcium and magnesium exposure despite potential reporting errors. Alternatively, dietary reporting of the Ca/Mg ratio is potentially non-specific and thus may be reflecting some other correlated factor linked with prostate cancer risk.
There are several limitations to address in this analysis. As pre-viously discussed, food frequency questionnaires have known limita-tions . Our case-control study design does not remove reverse causation as an alternative explanation. For example, the ‘magnesium trap’ hypothesis developed by Wolf and colleagues suggests cancer cells may pull magnesium from blood and retain high intracellular magne-sium levels necessary for cell proliferation . Since it is possible that metastasis to the bone could aﬀect circulating calcium and magnesium levels, we excluded men with known metastatic disease from analyses. Alternatives to the analysis of blood levels include a 24-h urine sample or nails, however these types of biospecimens were not available for this analysis. We did not have data on nonprescription and magnesium-rich medications (e.g., milk of magnesia), and we did not measure io-nized magnesium and calcium, vitamin D, insulin, blood cytokines, or other interesting biomarkers, but we may in the future . Race dif-ferences in magnesium levels reached a level of statistical significance, but the biological relevance of these diﬀerences in the context of car-diovascular disease or other morbidity is unclear.
In summary, we found a small but statistically significant diﬀer-ences in magnesium levels associated with race, such that black men had lower magnesium intake and lower blood magnesium levels than comparable white men. However, we found no evidence of a protective association between magnesium and prostate cancer in either black or white men.
Conflicts of interest
No author has a conflict of interest or any financial interests to disclose.
Appendix A. Supplementary data
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