In this large, ethnically diverse cohort of postmenopausal women, dietary magnesium intake was inversely associated with plasma concentrations of hs-CRP, IL-6, TNF-α-R2, sVCAM-1, and E-selectin independent of known risk factors for metabolic outcomes. Adjustment for dietary fiber intake attenuated but did not significantly alter these associations except in the case of E-selectin. After further adjustment for fruit and vegetable intake, folate intake, and saturated and trans fat intake, these inverse trends remained significant for hs-CRP, IL-6, and sVCAM-1, suggesting that dietary magnesium may influence concentrations of these biomarkers independently of other dietary factors associated with inflammation.
Our findings support the notion that magnesium intake improves systemic inflammation and endothelial dysfunction and may play a role in the prevention of type 2 diabetes and metabolic syndrome, a longstanding relation with causality yet to be confirmed. These data are consistent with a considerable body of experimental evidence in animals suggesting that acute magnesium deficiency leads to an inflammatory response (5
). Observational data in humans provide additional support for this relation. To date, several cross-sectional studies have reported a link between both low dietary magnesium intake (1
) and serum magnesium concentrations (19
) and elevated hs-CRP in white populations. Fiber intake and dietary patterns high in magnesium were also inversely associated with hs-CRP concentrations in the Nurses' Health Study (8
) and in NHANES 1999–2000 (20
). However, the relation of magnesium intake to IL-6 and TNF-α is less clear. No association was reported between dietary magnesium intake and TNF-α-R2 or IL-6 in the Nurses' Health Study (6
). However, a “western” dietary pattern, lower in magnesium-containing foods, was found to be associated with elevated IL-6 and other markers of inflammation and endothelial dysfunction (8
). Our findings provide evidence that hs-CRP and IL-6 may serve as sensitive markers of inflammation that may directly benefit from increased magnesium intake through dietary sources.
CRP is an acute-phase reactant secreted by the liver in response to inflammatory cytokines including IL-6 and TNF-α and is an independent predictor of cardiovascular disease (21
) and type 2 diabetes (11
). IL-6 and TNF-α are proinflammatory cytokines secreted by macrophages and T-cells to stimulate an immune response to trauma. Low plasma magnesium concentrations and the subsequent disruption in intracellular magnesium homeostasis may play a role in activating the inflammatory response (22
). Because hs-CRP is a more sensitive and robust marker of systemic inflammation than other inflammatory markers (23
), it may be more readily detected. Our findings also suggest that IL-6 may be sensitive to fluctuations in dietary intake of magnesium. Although TNF-α-R2, a cell surface receptor believed to modulate the action of TNF-α, was inversely associated with dietary magnesium intake before adjustment for dietary fiber intake, this relation was attenuated after adjustment, suggesting that the inverse association with TNF-α-R2 is most likely partially explained by the association with dietary fiber.
With regard to endothelial dysfunction, we observed that dietary magnesium was inversely associated with plasma concentrations of sVCAM-1 independently of other dietary factors. sVCAM-1 and sICAM-1 are cellular adhesion molecules belonging to the immunoglobulin family and are primarily involved in the attachment and transendothelial migration of leukocytes in response to inflammatory cytokines (24
). We observed no association between dietary magnesium intake and plasma concentrations of sICAM-1, a finding consistent with a cross-sectional study in the Nurses' Health Study (6
). However, we observed a modest association with sVCAM-1 that remained significant even after adjustment for dietary factors associated with endothelial dysfunction and cardiovascular disease. Although the biological explanation for the variability in results across markers is not clear, these findings further support the link between low magnesium intake and elevated concentrations of certain markers of endothelial dysfunction. E-selectin is a cellular adhesion molecule found primarily on the surface of stimulated endothelial cells and mediates the initial rolling of leukocytes along the endothelium (25
). In the current study, we observed an inverse association of dietary magnesium intake with E-selectin that disappeared after we accounted for dietary factors.
In this multiethnic cohort of women, we observed notable variation in strengths of association across ethnicity. To our knowledge, no previous work has examined potential ethnic differences in the relation of magnesium intake to systemic inflammation and endothelial dysfunction. Our findings of possible interactions in the current study should be interpreted with caution (i.e., hypothesis-generating) because ethnicity-specific sample sizes were small and the differences could partially be due to residual confounding from demographic and lifestyle factors. More importantly, the generally consistent patterns across the four ethnic groups provide additional evidence to support the notion that increased magnesium intake may have beneficial effects on alleviation of systemic inflammation and endothelial dysfunction. We also observed stronger associations of dietary magnesium intake with hs-CRP and IL-6 concentrations among subgroups with the highest concentrations of these inflammatory markers, i.e., overweight women and smokers. Similar findings among these high-risk subgroups were reported in the Women's Health Study (1
), suggesting that higher magnesium intake may be most beneficial among women who are predisposed to systemic inflammation.
There are several limitations that merit consideration. First, the measurement of dietary magnesium intake may be inaccurate because of self-report inconsistencies; however, magnesium intake assessed by our FFQ has a correlation of 0.7 when validated against dietary records (17
). Furthermore, in analyses that corrected for measurement error, the relation between magnesium intake and biomarkers was strengthened. Second, dietary magnesium intake is highly correlated with several nutrients including dietary fiber, potassium, and folate, and magnesium is found in high concentrations in foods such as whole grains, nuts, and fruits and vegetables. Therefore, parsing out the independent effects of dietary magnesium is a challenge. In the current study, we sought to examine the independent effects of dietary magnesium through adjustment for dietary fiber as well as fruit and vegetable intake, folate intake, and saturated and trans
fat intake in multivariable-adjusted models to control for potential confounding. Our findings suggest that dietary magnesium is associated with several markers of inflammation and endothelial dysfunction independent of these dietary factors, although we could not completely exclude the possibility of residual confounding. This, coupled with the cross-sectional design, does limit our ability to make causal inferences regarding the effect of magnesium intake on markers of inflammation and endothelial dysfunction.
In summary, we found that dietary intake of magnesium was independently and inversely associated with plasma concentrations of hs-CRP, IL-6, and sVCAM-1 in postmenopausal women. These findings are consistent with those of previous studies mostly in whites and support the notion that diets high in magnesium-rich foods including whole grains, nuts, and leafy green vegetables should be encouraged for metabolic disease prevention.