Magnesium intake and serum C-reactive protein levels in children

Magnesium Research 2007; 20 (1): 32-6 ORIGINAL ARTICLE Magnesium intake and serum C-reactive protein levels in children Dana E. King, Arch G. Mainous III, Mark E. Geesey, Tina Ellis Department of Family Medicine, Medical University of South Carolina, 295 Calhoun Street, Charleston, South Carolina 29425, USA Correspondence: Dana E. King, MD, MS. Tel.: 843 792 8112, fax: 843 792 3598 <kingde@musc.edu> Abstract. The objective of this study was to determine whether magnesium consumption is associated with inflammation (C-reactive protein [CRP]) in children. The study was an analysis of child (age 6-17 years) participants in the crosssectional, nationally representative National Health and Nutrition Examination Survey (NHANES). Children consuming less than 75% of RDA were 1.94 times more likely (p < 0.05) to have elevated serum CRP levels than children consuming above the RDA. In adjusted analyses controlling for demographics, cardiovascular risk factors, and BMI, children with consumption of less than 75% RDA were 58% more likely to have elevated CRP (OR 1.58, 95% CI 1.07- ). Children with intakes below the RDA are more likely to have elevated CRP levels. Key words: dietary magnesium, CRP, children, inflammation, cardiovascular Recent evidence strongly supports a significant role for inflammation in the development of cardiovascular disease in adults. Higher levels of inflammatory markers such as C-reactive protein (CRP) indicate increased cardiovascular (CV) risk [1-4]. According to data from the National Health and Nutrition Examination Survey (NHANES), the median serum CRP is 2.2 mg/l in adults and 0.4 mg/l in children under age 20 [5, 6]. CRP levels are highly correlated with cardiovascular risk factors in children, including blood pressure and BMI [6]. Previous research has indicated that dietary magnesium (Mg) intake may be a key component in the association between diet and inflammation [7]. Research in the adult population has documented that magnesium intake is inversely associated with systemic inflammation in middle-aged and older women [8]. Another study in adults of both sexes found a significant association between dietary Mg and likelihood of elevation of CRP that was independent of age, race, sex, BMI, and smoking [9]. Further, Guerrero-Romero et al. [10] have shown that low serum magnesium levels are independently related to elevated CRP concentration in non-diabetic, nonhypertensive obese subjects. More research is needed to evaluate the relationship between dietary Mg and serum CRP in children. 32 The objective of this study was to characterize the association between Mg intake and CRP in children who are and who are not overweight in a nationally representative sample of non-institutionalized US children of both sexes. Materials and methods We derived our study sample from the participants in the National Health and Nutrition Examination Survey 1999-2002 (NHANES 99-02), the most recent release of this nationally representative, complex, multistage, probability based survey of the civilian, non-institutionalized population of the US. Detailed information about the survey design, questionnaires, laboratory analyses, and examination methodology can be found on the website for the Centers for Disease Control, National Center of Health Statistics (http://www.cdc.gov/nchs/nhanes.htm). We limited our sample for this analysis to children aged 6-17 years who had valid measurements for both CRP and dietary intake of magnesium (n = 5007). High sensitivity C-reactive protein (CRP) was measured as part of the NHANES 99-02 physical and laboratory examination. Standard phlebotomy techniques were used to obtain specimens (see website). The threshold for elevated CRP was defined by doi: 10.1684/mrh.2007.0090

MAGNESIUM AND C-REACTIVE PROTEIN Table 1. US RDA for magnesium based on age and gender (US Office of Dietary Supplements of the National Institutes of Health). Age group (years) Boys Girls < 9 130 mg 130 mg 9-13 240 mg 240 mg > 13 410 mg 360 mg American Heart Association (AHA) guidelines that designate CRP levels 3.0 mg/l as associated with high cardiovascular risk in adults [4]; no such levels have been established for children.dietary intake in the NHANES 99-02 is based on recollection of foods eaten the previous day by the respondent coupled with known nutritional content of each of these foods (24 hour recall). The US Office of Dietary Supplements of the National Institutes of Health (http://ods.od.nih.gov/index.aspx) and the Institute of Medicine (IOM) have established Recommended Daily Allowances (RDA) of magnesium intake based on gender and age (table 1). For each child in the study population we calculated the percentage of the RDA that they had consumed based on gender and age. Three groups were established based on magnesium consumption: less than 75% of the RDA, 75-99% of the RDA, and 100% or more of the RDA. Demographic variables (age, race, sex) were included as control variables because of their known impacts on CRP [11]. Additional control variables were included that might be linked to eating behavior or also influence CRP level. We controlled for body weight (BMI > 85%ile) because of its link to diet and its known association with CRP [4, 6]. We also controlled for income level (above or below the poverty level), exercise, fiber intake, and calorie intake [9, 12]. Because the quantity of magnesium and fiber consumed may be linked to the total amount of food consumed, total caloric intake was incorporated as another control variable [5, 13]. Because of this complex sampling design, appropriate weighting factors (based on statistical stratification and population estimates) must be taken into account when calculating population-based frequency estimates. We used SUDAAN (Research Triangle Institute, Research Triangle, NC), a specialized statistical program that accounts for the complex weighting of the NHANES 99-02 sample [14]. Using SUDAAN allowed us to correct for unequal probabilities of selection and different response rates, ensuring that the results can be generalized to the noninstitutionalized civilian population of the U.S. Thus the percentages and odds ratios in this study represent weighted values. SUDAAN also adjusts the standard errors to account for the weighting, stratification, and clustering of the complex sampling design to ensure that expressed p values are valid [15]. Descriptive statistics for the sample were performed to illustrate the demographic characteristics and dietary magnesium intake. For each of the demographic variables (age, race, gender, etc.), the association with the dietary magnesium quartile group was examined using v 2 analyses. Magnesium intake then was examined in adjusted multivariate logistic regression analyses predicting elevated serum CRP ( 3.0 mg/l). The covariates age, race, gender, BMI, income, exercise, fiber intake, and total caloric intake were included in the models to control for their effects. Standardized betas, p-values, odds ratios, and 95% confidence intervals were obtained from the logistic regression output. Statistical significance was defined as 0.05 without correction for multiple-comparisons, since there was only one mineral examined, and the specific analyses were planned in advance. Results Of the 5007 children with available laboratory samples, 3236 (58.6%) had magnesium intake below the RDA (table 2). Only 38% of overweight children (> 85%ile) met or exceeded the RDA for Mg intake by age and gender, compared to 43% of normal weight children (< 85%ile), although the difference is not statistically significant (p = 0.07). Children with Mg intake < 75% of the RDA had a significantly greater median serum CRP (0.38 mg/l) compared to children above the RDA (0.25 mg/l) (p < 0.05). In unadjusted analyses, children < 75% RDA were 1.94 times more likely to have elevated CRP than children above the RDA (p < 0.05). In logistic regression analyses, controlling for age, race, sex, income level, exercise, fiber intake, BMI, and total calories, children with a consumption of < 75% of RDA were 58% more likely to have elevated CRP (OR 1.58, 95% CI 1.07-, table 3). Overweight children with Mg intake below the RDA were not more likely to have an elevated CRP than children with Mg intake above the RDA (table 3). Discussion The main finding of this study is that children are more likely to have elevated serum CRP (> 3.0 mg/l) if they consume less than the RDA of Mg. Overweight children had no greater likelihood of having elevated CRP. 33

D.E. KING, ET AL. Table 2. Demographics of children ages 6-17 in the US, according to the presence or absence of elevated serum CRP. Sample size of 5007 individuals representing a US population estimate of 41,089,564. Total Serum CRP < 3.0 mg/l Serum CRP 3.0 mg/l Dietary Mg intake 0.003 < 75% RDA 41.8% 85.8% 14.2% 75-99% RDA 16.9% 89.1% 10.9% RDA 41.4% 92.1% 7.9% Race 0.155 White 61.5% 90.2% 9.8% Black 15.0% 88.1% 11.9% Hispanic 19.2% 86.3% 13.7% Other 4.4% 86.8% 13.2% Gender 0.122 Male 51.4% 89.8% 10.2% Female 48.6% 88.1% 11.9% Household income 0.110 Below poverty 22.4% 86.7% 13.3% Above poverty 77.6% 89.6% 10.4% BMI < 0.001 <85 th percentile 68.3% 93.9% 6.1% 85 th percentile 31.7% 78.4% 21.6% Exercise 0.217 < 3x/week 19.0% 87.1% 12.9% 3x/week 81.0% 89.3% 10.7% v 2 p= The association between Mg intake and CRP was maintained after controlling for demographic and lifestyle factors that could confound the association. The implications of these findings are that Mg intake may be an important determinant of levels of inflammation in children and adolescents as it is in adults. Mg deficiency may play a role in putting individuals at increased cardiovascular risk at a young age. The findings also have some implications as to whether magnesium plays a direct and important role in regulating inflammation. Magnesium functions in many important metabolic pathways and is a coenzyme for almost 300 reactions including many involving muscle contraction. Magnesium has also been found to play a key role in endothelial metabolism and function [16]. Because children with elevated CRP frequently also have other accompanying cardiovascular risk factors, maintaining sufficient magnesium for important physiologic processes is especially important [6]. Healthier diet habits are needed to assure adequate magnesium intake in children for these vital metabolic pathways. Elevated CRP levels are also more common in children with symptoms of the metabolic syndrome [17]. Children with the metabolic syndrome were approximately three times more likely to have an elevated CRP level than children without the metabolic syndrome [17]. It is unknown whether children with an elevated CRP level are more likely to experience cardiovascular complications in the future. However, it will be important to assess the various cardiovascular risk factors into adulthood. Previous studies have demonstrated an association between diet and elevation of serum CRP. Most notably, high dietary fiber intake has been associated with lower CRP [9, 18, 19]. In those studies, other nutrients were not found to be associated with CRP levels, including carbohydrates and saturated fats [9, 18]. However, in some studies dietary fiber intake was found to be highly correlated with magnesium intake [9]. The question arises as to whether the lower levels of CRP are due to the intake of fiber, magnesium, or some other nutrient in foods that are a common source of both (e.g., bran). By controlling for fiber intake in the current study, we were able to test for and confirm an independent association with magnesium. The study has some important limitations that should be taken into account. First, dietary information was obtained from 24-hour dietary recall, which 34

MAGNESIUM AND C-REACTIVE PROTEIN Table 3. Likelihood (odds ratio and 95% confidence interval) of having elevated serum CRP (> 3.0 mg/l). All children BMI 85 th Percentile Odds ratio 95% CI Odds ratio 95% CI Fiber intake 0.982 0.956-1.008 0.989 0.952-1.026 Caloric intake 1.000 0.999-1.001 1.000 0.999-1.001 Age 1.005 0.948-1.066 1.040 0.973-1.112 Race White 1 1 1 1 Black 0.963 0.680-1.364 0.983 0.595-1.634 Hispanic 1.213 0.849-1.732 1.063 0.695-1.626 Other 0.957 0.474-1.935 1.083 0.411-2.856 Gender Male 1 1 1 1 Female 1.213 0.945-1.558 1.424 1.049-1.934 Income Below poverty 1.182 0.825-1.695 1.238 0.869-1.762 Above poverty 1 1 1 1 Exercise < 3x/week 1 1 1 1 3x/week 1.032 0.717-1.486 0.865 0.527-1.420 BMI <85 th percentile 1 1 85 th percentile 3.834 2.947- Mg Intake < 75% RDA 1.578 1.070-1.377 0.849-75-99% RDA 1.322 0.740-2.362 1.419 0.713-2.824 RDA 1 1 1 1 may not accurately represent an individual s intake over the last several weeks or months. Second, participants may have exaggerated or overestimated their intake of healthy foods such as vegetables and legumes which are relatively high in magnesium. However, if true, then population estimates of magnesium intake are likely to be too low, and the real associations between Mg and CRP may be stronger than we have illustrated. Third, the strength of the association between magnesium supplement intake and CRP is modest, and may be due to other unmeasured factors. Further, we can make no definitive statement regarding cause and effect in a crosssectional analysis. Conclusion In conclusion, magnesium intake below the RDA is prevalent and associated with a higher likelihood of elevated serum CRP in children. It may be beneficial to consider encouraging more magnesium intake in children by increasing the intake of magnesium-rich foods, but at present the scientific evidence does not support magnesium supplementation for the general population. Further prospective studies would need to be done to determine whether increased magnesium intake can lower inflammation and be of benefit to children s health. References 1. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97: 2007-11. 2. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis. JAMA 2001; 285: 2481-5. 3. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. NEnglJMed2002; 347: 1557-65. 4. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon III RO, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith Jr. SC, Taubert K, Tracy RP, Vinicor F, Centers for Disease Control and Prevention, 35

D.E. KING, ET AL. American Heart Association. AHA/CDC scientific statement. Markers of inflammation and cardiovascular disease-application to clinical and public health practice. Circulation 2003; 107: 499-511. 5. King DE, Egan BM, Mainous III AG, Geesey M. Elevation of C-reactive protein in people with prehypertension. J Clin Hypertens 2004; 6: 562-8. 6. Ford ES. C-reactive protein concentration and cardiovascular disease risk factors in children: findings from the National Health and Nutrition Examination Survey 1999-2000. Circulation 2003; 108: 1053-8. 7. Rayssiguier Y, Gueux E, Nowacki W, Rock E, Mazur A. High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation. Magnes Res 2006; 19: 237-43. 8. Song Y, Ridker PM, Manson JE, Cook NR, Buring JE, Liu S. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 2005; 28: 1438-44. 9. King DE, Mainous III AG, Geesey M, Woolson RF. Dietary magnesium and C-reactive protein levels. JAm Coll Nutr 2005; 24: 166-71. 10. Guerrero-Romero F, Rodriguez-Moran M. Relationship between serum magnesium levels and C-reactive protein concentration, in non-diabetic, non-hypertensive obese subjects. Int J Obes Relat Metab Disord 2002; 26: 469-74. 11. Ford ES, Giles WH, Myers GL, Rifai N, Ridker PM, Mannino DM. C-reactive protein concentration distribution among US children and young adults: findings from the National Health and Nutrition Examination Survey, 1999-2000. Clin Chem 2003; 49: 1353-7. 12. King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol 2003; 92: 1335-9. 13. Dube L, Granry JC. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can J Anaesth 2003; 50: 732-46. 14. Shah BV, Barnwell BG, Bieler GS. SUDAAN User s Manual (Release 7.0), Research Triangle Park. NC: Research Triangle Institute, 1996. 15. LaVange LM, Stearns SC, Lafata JE, Koch GG, Shah BV. Innovative strategies using SUDAAN for analysis of health surveys with complex samples. Stat Methods Med Res 1996; 5: 311-29. 16. Maier JA, Malpeuch-Brugere C, Zimowska W, Rayssiguier Y, Mazur A. Low magnesium promotes endothelial cell dysfunction: implications for atherosclerosis, inflammation and thrombosis. Biochim Biophys Acta 2004; 1689: 13-21. 17. Ford ES, Ajani UA, Mokdad AH. The metabolic syndrome and concentrations of C-reactive protein among U.S. youth. Diabetes Care 2005; 28: 878-81. 18. King DE, Buchanan T, Mainous AG, Pearson W. C-reactive protein and glycemic control in adults with diabetes. Diabetes Care 2003; 26: 1535-9. 19. Ajani UA, Ford ES, Mokdad AH. Dietary fiber and C-reactive protein: findings from national health and nutrition examination survey data. J Nutr 2004; 134: 1181-5. 36