Gail Rogers

Serum Total Homocysteine Concentrations in the Third National Health and Nutrition Examination Survey (1991-1994): Population Reference Ranges and Contribution of Vitamin Status to High Serum Concentrations

Homocysteine, a non-protein-forming sulfur amino acid, has attracted attention because elevated concentrations of circulating total homocysteine are associated with an increased risk for vascular disease (1, 2). Homocysteine is also a sensitive functional marker of inadequate cellular folate and vitamin B12 concentrations (3). Inadequate status of these vitamins has important health consequences that may be independent of their role in homocysteine metabolism. Low folate concentrations increase a womans risk for having a baby with a neural tube defect (4, 5), and an inadequate vitamin B12 concentration is known to produce various neurologic and cognitive effects (6, 7). Persons with low circulating folate or vitamin B12 concentrations have higher fasting total homocysteine concentrations (8-10), and elevated fasting total homocysteine concentrations are usually normalized by treatment with folic acid and vitamin B12 (6, 11-14). However, less is known about the importance of these vitamins as risk factors for high homocysteine concentration in the general population. Only three studies have examined the relation between homocysteine concentration and its vitamin determinants in samples that were designed to be representative of U.S. national (8) or regional (9, 10) populations. One of these studies (9) reported that approximately two thirds of all cases of moderately elevated total homocysteine concentrations were potentially attributable to low vitamin concentrations, but estimation of the proportion of cases with high homocysteine concentrations that can be attributed to inadequate vitamin status is complicated by the lack of a standard definition of a high total homocysteine concentration. In the absence of a definition based on increased risk for an adverse health outcome, such as vascular disease, upper reference limits from samples of healthy persons without established risk factors for high homocysteine concentrations have been used to define a high total homocysteine concentration (10, 15-17). We previously described the distribution of total serum homocysteine concentrations in participants 12 years of age or older from the third National Health and Nutrition Examination Survey (NHANES III), a population-based sample of U.S. residents (18). These data present a unique opportunity to develop population reference ranges for serum total homocysteine concentration and to determine the extent to which elevated homocysteine concentrations are associated with low circulating vitamin concentrations in a representative sample of U.S. residents. Methods Participants The NHANES III was developed to obtain nationally representative information on the health and nutritional status of the civilian, noninstitutionalized U.S. population (19, 20). Homocysteine concentrations were measured as part of an NHANES III surplus sera project on serum samples from participants 12 years of age or older who were seen during phase II of this survey (19911994). This project is described in greater detail elsewhere (18). Homocysteine concentrations were measured at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University by using the high-performance liquid chromatography method of Araki and Sako (21). The interassay coefficient of variation for this assay was 6%. Folate and vitamin B12 were determined for phase 2 specimens at the Centers for Disease Control and Prevention central laboratory by using a Quanta Phase II radioassay kit (Bio-Rad Laboratories, Hercules, California), and analyses are described in detail in the NHANES III Laboratory Procedures Manual (22). The coefficients of variation for folate and vitamin B12 were 6% and 7%, respectively. Informed consent was obtained from all respondents. The NHANES III protocol was approved by the National Center for Health Statistics NHANES Institutional Review Board, and measurement of serum homocysteine was approved by the Human Investigations Review Committee at the New England Medical Center. We used the following search strategy, combining Medical Subject Headings (MeSH terms) and text words, to identify all population-based studies relating vitamin status to circulating homocysteine concentrations: ([homocysteine (MeSH] OR homocysteine [Text Word]) AND (vitamins [MeSH] OR vitamin [Text Word]]) AND (epidemiologic studies [MeSH] OR data collection [MeSH] OR survey [Text Word]]. This search identified 137 citations, of which 16 were reviews. We selected original studies that 1) were designed to be representative of national, regional, or local populations and 2) described the relation between circulating homocysteine concentrations and either intake or circulating concentrations of folate or vitamin B12. As of 1 March 1999, 3 articles met our criteria (8-10). Statistical Analysis We used sample weights in analyses to account for unequal probability of selection and nonresponse and to produce estimates of means and percentiles that were representative of the noninstitutionalized, civilian U.S. population. We used SUDAAN statistical software (23) to account for the complex survey design in the variance estimates. Because total homocysteine, folate, and vitamin B12 values were skewed, logarithmic transformations were applied. To show the relations between total homocysteine concentrations and vitamin concentrations, we classified participants into age- and sex-specific vitamin decile categories and estimated the geometric mean of the serum total homocysteine concentration within each decile. Analyses were adjusted for ethnicity and serum creatinine concentration. In addition, the relation between total homocysteine and folate concentrations was adjusted for vitamin B12 concentrations, and the relation between total homocysteine and vitamin B12 was adjusted for folate concentrations. We tested the associations between homocysteine and vitamins for interactions with age, sex, and ethnicity. We tested for trend of total homocysteine concentration across vitamin concentrations by using linear regression with the logarithm of the continuous vitamin concentration as the independent variable, adjusting as described above. We showed the trend by using the SYSTAT LOWESS procedure to fit smoothed curves (24) to the geometric mean total homocysteine concentrations in the vitamin decile categories (25). It has been suggested that population reference ranges for the total homocysteine concentration be established in samples of persons without established risk factors for a high homocysteine concentration (10, 15-17). For our reference sample, we included persons whom we assumed to be folate- and vitamin B12-replete (that is, their serum concentrations of both vitamins were above the 50th percentile) and had normal serum creatinine concentrations (<90 mol/L for women and<110 mol/L for men). Pregnant women were excluded. We used the 5th and the 95th percentiles from the reference sample to estimate population reference ranges. To identify the potential impact of low vitamin concentrations on high total homocysteine concentration, we needed to establish values for high total homocysteine and low vitamin concentrations. We used the sex-specific 95th percentiles in the participants 20 to 39 years of age (the reference sample) to define high total homocysteine concentrations for all age groups. We used this reference sample because homocysteine concentrations changed little with age in this group, unlike in the other age groups (18). We defined low vitamin concentrations as a folate concentration less than 11 nmol/L (26, 27) and a vitamin B12 concentration less than 185 pmol/L (28, 29). We calculated the prevalence of high total homocysteine concentration; the prevalence ratio for high total homocysteine concentration; the attributable risk percentage; and the population attributable risk percentage for persons with low concentrations of folate, vitamin B12, or both compared with persons who had adequate concentrations of both of these vitamins. The attributable risk percentage estimates the excess cases of high homocysteine concentrations among persons with low vitamin concentrations, whereas the population attributable risk percentage takes into account the prevalence of low vitamin concentrations in the population and estimates the excess of high homocysteine concentrations associated with low vitamin concentrations in the entire population. We used the design effect for total homocysteine concentration, which is the ratio of the complex sampling design variance derived by using SUDAAN software (23) to the simple random sample variance calculated by using SAS software (30), to determine the recommended minimum sample size needed to achieve stable estimates of means, proportions, and percentiles according to the National Center for Health Statistics analytic guidelines (19). On the basis of an average design effect of approximately 1.4 for our sample, means and medians derived from fewer than 42 participants, 10th and 90th percentiles derived from fewer than 112 participants, and 5th and 95th percentiles derived from fewer than 224 participants were deemed unstable. Sample size for stable estimates of the proportions varied by the magnitude of the proportion, ranging from 42 for proportions of 0.5 to 224 for proportions of 0.05 or 0.95. We indicate in the text and tables statistics that did not meet the appropriate sample size. We categorized participants into three ethnic groups: non-Hispanic white, non-Hispanic black, and Mexican American. We excluded persons from other ethnic groups (n=436) because their inclusion produced unstable estimates of mean total homocysteine concentration after adjustment for ethnicity. Our analyses are based on 8086 participants with complete data on serum total homocysteine, folate, vitamin B12, and creatinine concentrations. Results Table 1 shows selected characteristics of the sample by sex and ethnic group. On average, non-Hispanic white pa

The Development of the Mediterranean-Style Dietary Pattern Score and Its Application to the American Diet in the Framingham Offspring Cohort

Previous Mediterranean diet scores were simple to apply but may not be appropriate for non-Mediterranean populations. We developed a Mediterranean-Style Dietary Pattern Score (MSDPS) to assess the conformity of an individuals diet to a traditional Mediterranean-style diet. The MSDPS is based on the recommended intakes of 13 food groups in the Mediterranean diet pyramid. Each food group is scored from 0 to 10 depending on the degree of correspondence with recommendations. Exceeding the recommendations results in a lower score proportional to the degree of overconsumption. The sum of the component scores is standardized to a 0-100 scale and weighted by the proportion of energy consumed from Mediterranean diet foods. We applied the MSDPS to dietary data collected at the 7th examination of the Framingham Offspring Cohort and tested the content validity of the score against selected nutrients known to be associated with the Mediterranean-style dietary pattern. The mean MSDPS was 24.8 (range, 3.1-60.7). Participants with a higher MSDPS were more likely to be women, older, multivitamin users, to have lower BMI and waist circumferences, and less likely to be current smokers. The MSDPS demonstrated content validity through expected positive associations with intakes of dietary fiber, (n-3) fatty acids, antioxidant vitamins, calcium, magnesium, and potassium, and inverse associations with those of added sugar, glycemic index, saturated fat, and trans-fat, and the (n-6):(n-3) fatty acid ratio. The MSDPS is a useful instrument to measure overall diet quality according to the principles of a Mediterranean-style dietary pattern.

Whole-Grain Intake and Cereal Fiber Are Associated with Lower Abdominal Adiposity in Older Adults

Foods high in dietary fiber may play an important role in regulating body weight. Few observational studies have examined the relationship between dietary fiber from different sources and body fat in older adults. Our objectives were to examine the associations among grain intake (whole and refined), dietary fiber and fiber sources, and body fat among older adults. We used data from 434 free-living adults (177 men and 257 women) aged between 60 and 80 y. Dietary intake was estimated from a 126-item semiquantitative FFQ. Percent body fat and percent trunk fat mass were measured by whole-body dual-energy X-ray absorptiometry. After adjustment for covariates, whole-grain intake was inversely associated with BMI [26.8 kg/m(2) (25.7-28.1) vs. 25.8 kg/m(2) (24.6-27.1), (95% CI); P-trend = 0.08], percent body fat [34.5% (32.7-36.3) vs. 32.1% (30.1-34.1); P-trend = 0.02], and percent trunk fat mass [43.0% (40.4-45.5) vs. 39.4% (36.7-42.1); P-trend = 0.02] in the lowest compared with the highest quartile category of whole-grain intake. Refined grain intake was not associated with any measure of body fat distribution. Cereal fiber was inversely associated with BMI [27.3 kg/m(2) (26.1-28.6) vs. 25.4 kg/m(2) (24.3-26.7); P-trend = 0.012], percent body fat [34.7% (32.8-36.6) vs. 31.5% (29.4-33.5); P-trend = 0.004], and percent trunk fat mass [42.8% (40.2-45.4) vs. 37.8% (35.0-40.6); P-trend = 0.001]. No significant association was observed between intakes of total fiber, vegetable or fruit fiber, and body composition measurements. Higher intakes of cereal fiber, particularly from whole-grain sources, are associated with lower total percent body fat and percent trunk fat mass in older adults.

Longitudinal association between dairy consumption and changes of body weight and waist circumference: the Framingham Heart Study

Background:Dairy foods are nutrient dense and may be protective against long-term weight gain.Objective:We aimed to examine the longitudinal association between dairy consumption and annualized changes in weight and waist circumference (WC) in adults.Methods:Members of the Framingham Heart Study Offspring Cohort who participated in the fifth through eighth study examinations (1991–2008) were included in these analyses (3440 participants with 11 683 observations). At each exam, dietary intake was assessed by a validated food frequency questionnaire, and weight and WC were assessed following standardized procedures. Repeated measures models were used for the longitudinal analyses of annualized weight and waist circumference changes, adjusting for time-varying or invariant covariates.Results:On average, participants gained weight and WC during follow-up. Dairy intake increased across exams. After adjusting for demographic and lifestyle factors (including diet quality), participants who consumed ⩾3 servings per day of total dairy had 0.10 kg (±0.04) smaller annualized increment of weight (Ptrend=0.04) than those consuming <1 serving per day. Higher total dairy intake was also marginally associated with less WC gain (Ptrend=0.05). Similarly, participants who consumed ⩾3 servings per week of yogurt had a 0.10 kg (±0.04) and 0.13 cm (±0.05) smaller annualized increment of weight (Ptrend=0.03) and WC (Ptrend=0.008) than those consuming <1 serving per week, respectively. Skim/low-fat milk, cheese, total high-fat or total low-fat dairy intake were not associated with long-term change in weight or WC.Conclusion:Further longitudinal and interventional studies are warranted to confirm the beneficial role of increasing total dairy and yogurt intake, as part of a healthy and calorie-balanced dietary pattern, in the long-term prevention of gain in weight and WC.

Dietary Carbohydrates and Cardiovascular Disease Risk Factors in the Framingham Offspring Cohort

Objective: Evidence from observational studies has suggested that carbohydrate quality rather than absolute intake is associated with greater risk of chronic diseases. The aim of this study was to examine the relationship between carbohydrate intake and dietary glycemic index and several cardiovascular disease risk factors. Methods: We examined cross-sectional associations between total carbohydrate and dietary glycemic index (GI) intakes and several cardiovascular disease risk factors (CVD) in a sample of 2,941 Framingham Offspring Participants. CVD risk factors included waist, blood pressure, lipids, fasting insulin, fasting glucose, and the insulin sensitivity index (ISI0,120). Dietary intake was assessed by a food frequency questionnaire (FFQ) and categorized by quintiles of dietary intake. Results: After adjustment for potential confounding factors, dietary GI was positively associated with fasting triglycerides (mean: 115mg/dL in the lowest and 127 mg/dL in the highest quintile of intake; P for trend < 0.001), fasting insulin (26.8 and 28.9 μu/mL, respectively, P for trend < 0.0001), and inversely associated with HDL cholesterol (49 and 47 mg/dL, respectively, P for trend 0.003) and ISI0,120 (26.8 and 25.1, P for trend < 0.001). There was no significant relationship between dietary GI and waist circumference, total cholesterol, LDL cholesterol and fasting glucose. Intakes of total carbohydrate were inversely associated with waist circumference and HDL cholesterol, and positively associated with fasting triglycerides. Conclusion: These cross-sectional findings support the hypothesis that a high GI diet unfavorably affects CVD risk factors and therefore, substitution of high with low GI dietary carbohydrates may have reduce the risk of CVD.

Higher Dietary Flavonol Intake Is Associated with Lower Incidence of Type 2 Diabetes

Substantial experimental evidence suggests that several flavonoid classes are involved in glucose metabolism, but few clinical or epidemiologic studies exist that provide supporting human evidence for this relationship. The objective of this study was to determine if habitual intakes of specific flavonoid classes are related to incidence of type 2 diabetes (T2D). We followed 2915 members of the Framingham Offspring cohort who were free of T2D at baseline from 1991 to 2008. Diabetes was defined by either elevated fasting glucose (≥7.0 mmol/L) or initiation of hypoglycemic medication during follow-up. Dietary intakes of 6 flavonoid classes and total flavonoids were assessed using a validated, semiquantitative food frequency questionnaire. We observed 308 incident cases of T2D during a mean follow-up period of 11.9 y (range 2.5–16.8 y). After multivariable adjusted, time-dependent analyses, which accounted for long-term flavonoid intake during follow-up, each 2.5-fold increase in flavonol intake was associated with a 26% lower incidence of T2D [HR = 0.74 (95% CI: 0.61, 0.90); P-trend = 0.003] and each 2.5-fold increase in flavan-3-ol intake was marginally associated with an 11% lower incidence of T2D [HR = 0.89 (95% CI: 0.80, 1.00); P-trend = 0.06]. No other associations between flavonoid classes and risk of T2D were observed. Our observations support previous experimental evidence of a possible beneficial relationship between increased flavonol intake and risk of T2D.

Higher dietary anthocyanin and flavonol intakes are associated with anti-inflammatory effects in a population of US adults

Background: Although growing evidence from trials and population-based studies has supported a protective role for flavonoids in relation to risk of certain chronic diseases, the underlying mechanisms remain unclear. Several previous studies focused on individual inflammatory biomarkers, but because of the limited specificity of any individual marker, an assessment of a combination of biomarkers may be more informative. Objective: We used an inflammation score (IS) that integrated 12 individual inflammatory biomarkers for the examination of associations with intakes of different flavonoid classes. Design: The study was a cross-sectional analysis of 2375 Framingham Heart Study Offspring Cohort participants. Intakes of total flavonoids and their classes (anthocyanins, flavonols, flavanones, flavan-3-ols, polymers, and flavones) were calculated from validated food-frequency questionnaires. Individual inflammatory biomarkers were ranked, standardized, and summed to derive an overall IS and subgroup scores of functionally related biomarkers. Results: In multivariate analyses, an inverse association between higher anthocyanin and flavonol intakes and IS was observed with a mean ± SE difference between quintile categories 5 and 1 of −1.48 ± 0.32 (P-trend ≤ 0.001) and −0.72 ± 0.33 (P-trend = 0.01), respectively. Results remained significant after additional adjustment for physical activity and vitamin C and fruit and vegetable intakes. Higher anthocyanin intake was inversely associated with all biomarker subgroups, whereas higher flavonol intake was associated only with lower cytokine and oxidative stress biomarker concentrations. In food-based analyses, higher intakes of apples and pears, red wine, and strawberries were associated with a lower IS with differences between quintiles 5 and 1 of −1.02 ± 0.43 (P = 0.006), −1.73 ± 0.39 (P < 0.001), and −0.44 ± 0.88 (P = 0.02), respectively. Although intakes of other classes were not associated with a reduction in overall IS, higher intakes of flavan-3-ols and their polymers were associated with a significant reduction in oxidative stress biomarkers. Conclusion: These findings provide evidence to suggest that an anti-inflammatory effect may be a key component underlying the reduction in risk of certain chronic diseases associated with higher intakes of anthocyanins and flavonols. The Framingham Offspring Study was registered at clinicaltrials.gov as NCT00005121 (Framingham Heart Study).

Prevalence and predictors of children's dietary supplement use: the 2007 National Health Interview Survey

BACKGROUND Little is known about the characteristics of US children who are dietary supplement users. OBJECTIVE We described the prevalence and predictors of and reasons for giving children dietary supplements. DESIGN The study included children <18 y of age who participated in the Complementary and Alternative Medicine supplement of the National Health Interview Survey of 2007 whose proxies provided complete information on child dietary supplement use. RESULTS A total of 37% of subjects used dietary supplements, 31% of subjects used multivitamin mineral (MVM) products exclusively, 4% of subjects used single vitamins or minerals solely or in combination with MVMs, and 2% of subjects used nonvitamin, nonmineral products either solely or in combination with other supplements. Users were more likely than nonusers to be Asian, white, or non-Hispanic; belong to families with higher parental education and income levels; reside in areas other than the South; be in good, very good, or excellent health; have private health insurance; and have a usual place at which they received conventional medical care. Children (3%) with the most disease burden and health care were more likely to use supplements than were healthier children. Supplements were given for the prevention or treatment of many illnesses and conditions. Neither the caregivers reasons nor specific supplements used were consistently associated with particular conditions. CONCLUSIONS The 37% of US children who used any type of dietary supplements differed from nonusers in family socioeconomic status and many other health-related characteristics. Users were given supplements to prevent or treat many illnesses and conditions for which there is only limited evidence of their efficacy.

Magnesium intake is related to improved insulin homeostasis in the framingham offspring cohort

Objective: Higher dietary intake of magnesium may protect against development of type 2 diabetes. The aim of this study was to examine the association between dietary magnesium intake and metabolic risk factors for diabetes. Methods: We examined cross-sectional associations between magnesium intake and fasting glucose and insulin, 2-hour post-challenge plasma glucose and insulin, and insulin resistance assessed by the homeostasis model (HOMA-IR) in 1223 men and 1485 women without diabetes from the Framingham Offspring cohort. Magnesium intake was assessed by a food frequency questionnaire and magnesium intake was categorized into quintile categories. Geometric mean insulin, glucose, 2-hour post challenge plasma glucose and insulin concentrations and HOMA-IR were estimated across quintile categories of magnesium intake using Generalized Linear Models. Results: After adjustment for potential confounding factors, magnesium intake was inversely associated with fasting insulin (mean: 29.9 vs 26.7 μU/mL in the lowest vs highest quintiles of magnesium intake; P trend <0.001), post-glucose challenge plasma insulin (86.4 vs 72 μU/mL; P trend <0.001), and HOMA-IR (7.0 vs 6.2; P trend <0.001). No significant association was found between magnesium intake and fasting glucose or 2-hour post challenge glucose. Conclusions: Improved insulin sensitivity may be one mechanism by which higher dietary magnesium intake may reduce the risk of developing type 2 DM.

Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study.

BACKGROUND Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts. OBJECTIVE We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimers disease (AD), MRI markers of brain aging, and neuropsychological function. METHODS Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n = 1663), multiple neuropsychological tests (n = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139). RESULTS In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β= -0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. CONCLUSIONS In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.