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Journal of the American College of Nutrition, Vol. 24, No. 6, 503-509 (2005)
Published by the American College of Nutrition

Serum Homocysteine Concentration of US Adults Associated with Fortified Cereal Consumption

Won O. Song, PhD, Chin-Eun Chung, PhD, Ock Kyoung Chun, PhD and Susan Cho, PhD

Dept. Food Science and Human Nutrition, Michigan State University, East Lansing (W.O.S, C.-E.C., O.K.C.)
Nutrition Business Partner and Director of Nutrition, WK Kellogg Institution, Battle Creek (S.C.), Michigan

Address reprint requests to: Won O. Song, PhD, MPH, RD, Rm 131, G.M. Trout Bd., Michigan State University East Lansing, MI, 48824. E: mail: song{at}msu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Background: Elevated serum total homocysteine (tHcy) concentration is implicated in the etiology of cardiovascular disease (CVD). A significant food source of B-vitamins involved in homocysteine metabolism is ready-to-eat cereal (RTEC) in the U.S.

Objective: To test the hypothesis that tHcy concentration is inversely associated with RTEC intake and blood B-vitamin levels in the U.S. general population.

Design: A cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES 1999–2000). Data were stratified according to age and gender. Men and women ≥ 19 y (n = 4,218) were classified as RTEC consumers (RTEC-C; n = 824) and RTEC non-consumers (RTEC-NC; n = 3,394) based on 24-hr dietary recall.

Results: Forty nine percent of participants showed folate intake with below the estimated average requirements (EARS). Serum folate and red blood cell (RBC) folate concentrations were increased with age in both genders, and significantly higher among RTEC-C than RTEC-NC (p < 0.05). Mean tHcy concentration increased with age, and was significantly lower among both men and women RTEC-C than among RTEC-NC. In multivariate linear regression analyses, RTEC consumption strongly predicted serum folate and tHcy concentrations.

Conclusion: tHcy concentrations were significantly lower in RTEC-C among the majority of age/gender groups than in RTEC-NC. RTEC consumption may potentially reduce the risk for CVD, mediated through tHcy.

Key words: ready-to-eat-cereal, fortification, homocysteine, folate, vitamin B-12, vitamin B-6


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Serum total homocysteine (tHcy) concentration has been associated with congestive heart failure [1], cardiovascular diseases (CVD) [2] and stroke [3]. Increasing evidence points to tHcy as an independent coronary risk factor [4–6]. Homocysteine can be converted back to methionine in a betaine-dependent reaction or a vitamin B-12 (as methyl-cobalamin) and folate (as 5-methyl tetrahydrofolate)-dependent reaction [7]. To be further metabolized in the body, homocysteine also needs a series of vitamin B-6-dependent reactions.

Elevated tHcy is involved in the conversion of cholesterol to low-density lipoprotein (LDL) and increases blood clotting [8]. Consequently, the American Academy of Family Physicians [8] set tHcy ≤ 12 µmol/L as desirable, and 12–15 µmol/L as an acceptable level for health in the absence of additional cardiovascular risk factors. Recommended treatment to prevent CVD includes a daily intake of a multivitamin with 400 µg folate, along with a supplementary 8 week regimen of an additional 800 µg folate. The American Heart Association [9] recommends a balanced diet including adequate folate, vitamin B-12, and vitamin B-6 required in the metabolism of tHcy. Dietary modification to increase folate intake from food sources is recommended prior to supplementation. Breakfast ready-to-eat-cereal (RTEC) has been a significant food source of folate and other B-vitamins in the American diet for decades.

The implementation of folate fortification of RTEC as well as cereal grain products was intended to increase folate intake among childbearing-aged women to reduce their risk of neural tube birth defect (NTD)-affected pregnancies [10]. Several studies have been focused on reducing tHcy concentration, a risk factor of CVD, by increased folate intake through FDA-mandated enrichment of cereal grain products with folate [11,12] and folate fortification of RTEC [13–17]. These studies were, however, conducted with selected subjects [12–15] in observational or experimental feeding study designs [12,15,16] and/or with different dietary intake data collection methods [11–14,17].

Expanding the reported cause and effect relationship between nutrient intake, nutritional status and CVD risk, we aimed to investigate the association among tHcy and consumption of fortified RTEC, a major source of B-vitamins in American diets. We analyzed the RTEC consumption patterns of a nationally representative cohort of U.S. adults from the 1999–2000 National Health and Nutrition Examination Survey (NHANES 1999–2000) and evaluated the association of RTEC consumption with the decreased tHcy concentrations. Authors assert that the data source is the most appropriate to test the hypotheses in the public health arena in order to establish dietary patterns related to biomarkers of known CVD risk factors.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Data Set
The NHANES 1999–2000 is the most recent population-based nutritional study conducted by the National Center for Health Statistics (NCHS) Centers for Disease Control and Prevention. This is the first national survey conducted after folate fortification in the U.S. The survey was conducted with a stratified, multistage probability sample of non-institutionalized civilians of the U.S. population. The survey used standardized questionnaires and physical examinations; in addition, blood samples were obtained and analyzed. Bilingual interviewers administered the questionnaires at participants’ home or at the mobile examination centers. Physical examinations included measurement of standing height and weight. Trained interviewers collected food intake information by asking what they had eaten over the previous 24-hour period. The data and corresponding documentation for the survey interview and examination components are reported in the website [18].

Study Design
The original NHANES 1999–2000 contains 9,965 individuals’ data of all race and ethnicity, and all age beginning 1 month and older. Excluded from the original database for the present study were the subjects younger than 19 y of age, pregnant women, or those reported to have unreliable dietary recall data by NCHS. Relevant data of the remaining 4,218 respondents were used in our statistical analyses by applying correct sample weight to derive inferences for the nationally representative population. Participants (4,218 adults, aged ≥ 19 y) were divided into two groups according to RTEC consumption based on 24-hr dietary recalls ("RTEC consumers", RTEC-C vs. "RTEC non-consumers", RTEC-NC). Participants were further divided by gender and age groups.

Individual food intake data based on 24-hr recalls and the USDA National Nutrient Database [19] were used to estimate average daily intakes of nutrients, including total energy, protein, carbohydrate, total fat, cholesterol, minerals (calcium, magnesium, phosphorus, zinc, and iron), and vitamins (folate, vitamin B-6, vitamin B-12, and vitamin C) for each participant. Comparative nutrient standards for our study included the estimated average requirements (EARs) which are nutrient intakes estimated to meet the requirement of half the healthy individuals in a particular life-stage and gender group [20].

Laboratory data in NHANES 1999–2000 including serum folate and RBC folate, vitamin B-12 and tHcy, were available from whole blood and sera. Prior to the phlebotomy, a questionnaire was administered to document and determine fasting compliance. Detailed specimen collection and processing instructions are discussed in the Manual for Medical Technicians. The analytical methods used by each of the participating laboratories are detailed in the manual [21].

Other variables that we controlled as they may affect tHcy were age, gender, BMI, smoking (%) and dietary supplement use (%). Subjects who smoked cigarettes "everyday" or "some days" were considered as "smoker". "Dietary supplements use" was defined as those who responded "yes" to a question "Any dietary supplements taken during last thirty days?"

Statistical Analyses
All data analyses were carried out using the SAS, release 8.02 (SAS Institute Inc, Cary, NC) and Survey Data Analysis for multi-stage sample designs professional software package (SUDAAN, release 8.01, Research Triangle Institute, Research Triangle Park, NC) [22]. SUDAAN was used to increase the accuracy and validity of the results through computing variance estimates and test statistics for a stratified, multistage probability survey design. Sample weights were applied to all analyses to account for the unequal probability of selection, noncoverage, and nonresponse bias resulting from over-sampling of low-income persons, adolescents, the elderly, African-Americans and Mexican-Americans.

The Jackknife procedure for variance approximation, specifically the "leave-one" or JK-1 procedure [23–25] was used to estimate sampling errors for NHANES 1999–2000. T-test was used to determine the statistical significance between RTEC-C and RTEC-NC using Jackknife variance estimation method. Multiple linear regressions were performed to predict the serum folate and tHcy concentration. Regression coefficients were estimated using the Jackknife variance estimator after multivariate adjustment for confounding factors and t-tests were used to determine if the regression coefficient was zero.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Dietary Characteristics of Subjects
Daily nutrient intake of RTEC-C was significantly higher than that of RTEC-NC for all nutrients examined except cholesterol and energy intake from fat (p < 0.05) (Table 1). Compared to the RTEC-NC group, the RTEC-C group had higher mean intakes of folate, vitamin B-6 and B-12 (522 vs. 334 µg, 2.7 vs. 1.7 mg, 5.9 vs. 4.6 µg, respectively).


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  		Table 1. Daily Dietary Intakes among 4,218 US Adults Aged 19+ y from NHANES 1999–20001

 
Nutrient Intakes
Forty nine percent of participants showed folate intake with below the estimated average requirements (EARs). Eighteen% of RTEC-C and 56.1% of RTEC-NC did not meet the EAR for folate (Table 1). On the other hand, 3.6% of RTEC-C and 1.1% of RTEC-NC demonstrated the consumption over the upper limit (UL) for folate (Table 1). Mean folate consumption was below the EAR among RTEC-NC in all age women, which was especially pronounced in women, where mean folate intake was ≤ 90% of the EAR (Table 2).


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  		Table 2. Nutrient Intakes and Blood Concentrations of RTEC-C and RTEC-NC in Age and Gender Subgroups

 
Nine% of RTEC-C and 36.3% of RTEC-NC did not meet the EAR for vitamin B-6 (Table 1). Across all age and gender subgroups, RTEC-C showed significantly higher intakes than those of RTEC-NC for vitamin B-6 (Table 2). Vitamin B-6 intakes in all age and gender groups exceeded the EAR requirements (Table 2).

RTEC-C of all age and gender subgroups consumed significantly higher intakes of vitamin B-12 than those of RTEC-NC (Table 2). 11.8% of RTEC-C and 29.2% of RTEC-NC did not meet the EAR for vitamin B-12 (Table 1).

Serum Nutrient Concentrations
RTEC-C had significantly higher mean serum and RBC folate concentrations in all age and gender subgroups than RTEC-NC (p < 0.05) (Table 2). Only 0.8% of RTEC-NC had serum folate below 6.8 nmol/L, whereas no RTEC-C had below 6.8 nmol/L (p < 0.05). Among reproductive age women of 19–50 y, RTEC-C showed higher mean RBC folate concentration than that of RTEC-NC (757.9 vs. 618.0 nmol/L, respectively, p < 0.001) (Table 2).

Among men of 19–50 y, RTEC-C had significantly higher serum vitamin B-12 concentrations (388.6 pmol/L) than RTEC-NC (352.4 pmol/L) (p < 0.05) (Table 2). Only 2.2% of RTEC-C and 2.6% of RTEC-NC had serum vitamin B-12 < 150 pmol/L with no statistical difference between the two groups.

Total Serum Homocysteine Concentrations
Mean tHcy concentration of all subjects was 8.3 µmol/L and tHcy concentrations in both men and women increased with advances in age (Table 2). Mean tHcy (µmol/L) concentrations of RTEC-C for ages 19–50 y and 51+ y were 7.5/6.3 (men/women) and 9.6/8.4 (men/women), respectively (Table 2). Mean tHcy (µmol/L) concentrations for the same ages of RTEC-NC were 8.4/6.9 (men/women), and 11.0/9.0 (men/women), respectively. Although in all age and gender subgroups, RTEC-C exhibited lower tHcy concentrations than RTEC-NC, only the age subgroups of 19–50 y showed statistically significant differences in mean tHcy concentrations. RTEC-C demonstrated significantly lower percentages of person with high-tHcy (> 13 µmol/L) than RTEC-NC in subgroups of men (19–50 y) and women (19+ y) (Table 2).

Relationships of RTEC Consumption with Total Serum Homocysteine Concentrations
In a multivariate analysis for serum folate (Table 3), RTEC consumption was a significant predictor for high serum folate concentrations (p < 0.05). Age, gender, BMI, smoking, dietary supplement use and RBC folate were other independent predictors of serum folate concentrations (p < 0.05).


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  		Table 3. Multivariate Predictive Model for Serum Folate Concentrations in US Adults Aged 19+ y: NHANES 1999–2000 (n = 4,218)

 
In multiple linear regression analyses, RTEC consumption, age, gender, dietary supplement use and vitamin B-12 intake demonstrated strong predictive values for tHcy concentrations (p < 0.05) and BMI, smoking, serum folate, and RBC folate were also independent predictors for tHcy concentrations (p < 0.1) (Table 4).


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  		Table 4. Multivariate Predictive Model for Serum Hcy Concentrations in US Adults Aged 19+ y: NHANES 1999–2000 (n = 4,218)

 

   DISCUSSION
 
Even after the enactment of folate fortification in grains (140 µg/100 g) in January 1998 [8] inadequate folate intake seems to persist in U.S., particularly among RTEC-NC and among childbearing age women. The rates of inadequate folate intake from food sources among women aged 19–50 y were 57.6% overall, 19.44% RTEC-C and 65.6% RTEC-NC groups in this study (data not shown). RTEC alone might not be a successful solution to control the risk of NTDs since only 17% of U.S. women aged 19–50 y consumed fortified RTEC.

Many investigators [26,27] reported benefits of educating the public on folate content of foods, and RTEC as a source of zinc, iron, folate and vitamin B-6. RTEC in the U.S. contains 11–2,070 µg folate per serving [19] with a mean 400 µg folate/serving. Recently, Quinlivan and Gregory [28] reported that estimated folate consumption from fortified foods is 215–240 µg daily. The recent U.S. fortification has brought a rapid improvement of folate status of American.

Others [29,30] have expressed pros and cons about potential effects of high intake of folate in specific sub-population groups. Only 3.6% of RTEC-C group in this study had estimated folate intake over the upper limit (UL, 1000 µg/day). To our knowledge, the potential adverse effects of long-term high folate intake have not yet been reported in a population-based study.

RTEC-C had significantly greater mean serum and RBC folate concentrations in all age and gender subgroups than RTEC-NC had. The rate of serum folate <6.8 nmol/L [31] was lower in RTEC-C than in RTEC-NC. The Centers for Disease Control and Prevention reported that the mean RBC folate concentration in women aged 15–44 y prior to folate fortification (1988–1994) was increased from 410 nmol/L to 714 nmol/L after fortification in 1999 [32]. The amount of folate intake needed to improve serum or RBC folate and tHcy seem to vary: 100 µg folate supplementation in subjects with >8.0 µmol/L initial tHcy [33]; 100 µg folate from fortified RTEC [34]; 800 µg folate in subjects with ischemic heart disease [35]; or adherence to the Dietary Approaches to Stop Hypertension (DASH) [36]; 600 µg folate daily intake [37]; or 499–665 ug folate from RTEC by CAD subjects [15].

Bioavailability of folate also varies among sources of folate. In a New Zealand trial [38], tHcy concentration was lowered more effectively by folate supplements and folate fortified breakfast cereals than by folate rich food. Varied bioavailability of folate from foods was offered as a possible explanation of the result.

In our present study, the RTEC-C group exhibited a higher plasma folate and lower tHcy concentration than the RTEC-NC group. In multivariate linear regression analyses, RTEC consumption retained significant predictive value for serum folate and tHcy concentrations.

Although present study didn’t show any significant inverse association between the blood level of vitamin B-12 with tHcy concentration, evidences of the relationships has been inconsistent: An observational study in CAD patients showed that serum levels of folate, but not vitamin B-6 or B-12, was a strong predictor of tHcy concentration [39]. Framingham Heart Study cohort reported that tHcy exhibited strong inverse association with plasma folate and weaker association with serum vitamin B-12 and B-6 [11]. On the contrary, in the study by Ganji and Kafai [40], increased serum vitamin B-12 concentration was associated with reduced tHcy.

The present study did not include nutrient intake originated from dietary supplements in our estimates of B vitamins and distinctions of natural and synthetic folate sources were not made. Dietary supplements are the major source of B-vitamins which are very important factor of tHcy level. The NHANES dataset on dietary supplements that was recently released in October 2004 describe levels of minerals, vitamins and other nutrients in selected supplements, but not in various other plant extracts-, antioxidant-based or functional supplements. Therefore, we decided to use the subjects’ self-reported categorical response to the question on supplement use as a proxy of dietary/health behavior, and focus on the folate intake from foods including RTEC. In addition, our results should be carefully interpreted based on the limitation of the nature of the cross-sectional design of NHANES 1999–2000 and 24-hr dietary recalls and the fact that less than 20% participants consumed RTEC.

In summary, we found that RTEC consumption was significantly related with increase of serum and RBC folate concentrations as well as intakes of folate, vitamin B-6 and B-12, and with reducing of tHcy concentration and dietary intake of fortified cereals associated with effectively improved nutritional status and reduced risks for CVD.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
Dr. Won O. Song was largely responsible for execution of the research project and Dr. Chin-Eun Chung completed the data analysis while working as a visiting scholar in the Food and Nutrition Database Research Center (FNDRC) at Michigan State University. Dr. Ock Kyoung Chun, a research associate in FNDRC, completed the manuscript with additional data analysis. All authors contributed to the writing of the manuscript, and certify that they will take public responsibility for the content and provide any relevant data upon request. The authors also certify that each author contributed substantially to the conception, design, analyses and interpretation of the data, drafting and revision of the content, and approval of the final version. Authors of this paper confirm that the content has not been published elsewhere and does not overlap with any published work.

Received October 14, 2004. Accepted September 14, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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