FOLIC ACID FORTIFICATION: HOW LOW A DOSE?
Tighe P, Ward M, McNulty H, Finnegan O, Dunne A, Strain J, Molloy AM, Duffy M, Pentieva K, and Scott JM. A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy. Am J Clin Nutr 2011;93:11–18.
High dietary levels of folate are associated with reduced risks for cancer, neural tube defects, and heart disease. In recent years, many countries have implemented mandatory fortification of grain products with folic acid, with the primary goal of reducing the incidence of neural tube defects. Folic acid fortification in these countries has also reduced circulating homocysteine levels, a biomarker for vascular disease. It has been hypothesized that by lowering homocysteine levels, a concomitant reduction in cardiovascular disease would be seen, although intervention trials have been largely disappointing. Some work indicates that lowering homocysteine through folic acid supplementation may reduce the incidence of stroke, particularly in individuals with greater reductions in homocysteine levels. However, other work suggests that overexposure to folic acid may be harmful, particularly with respect to colorectal cancer and some forms of breast cancer. Therefore, it is important to establish a level of fortification that maximizes the positive effects of folic acid fortification, such as homocysteine lowering, and minimizes risk of overexposure. Tighe et al. examined the utility of long-term, low-dose folic acid supplementation for lowering homocysteine in both healthy individuals and those with ischemic heart disease.
Participants were recruited from a cardiac rehabilitation program and local residents in Ulster, Northern Ireland, where there is no mandatory folic acid fortification. Participants with ischemic heart disease (IHD) (n = 101) and healthy volunteers (n = 71) were randomly assigned to either the folic acid (200, 400, or 800 μg/d) or placebo conditions for 26 weeks. (For reference, the US recommended dietary allowance for folic acid is 400 μg/d.) Homocysteine levels of all participants were measured at baseline and at week 26. Participants were categorized into low or high baseline homocysteine groups. IHD participants had additional measures taken at 6 or 12 weeks after beginning the trial. The primary outcome measure was change in homocysteine from baseline.
In participants with high initial homocysteine levels (16.6 µmol/L), supplementation with folic acid reduced total homocysteine by approximately 20–27% compared to individuals in the placebo group. For individuals with low initial homocysteine levels (10.1 µmol/L), supplementation with folic acid reduced total homocysteine by approximately 8% compared to placebo. There were no differences in total homocysteine lowering among recipients of the three doses of folic acid; however, there was a dose-dependent relationship on the time course of homocysteine lowering. Maximal reductions in homocysteine were seen at 6 weeks with the highest dose (800 μg), at 12 weeks with the standard recommended dose (400 μg), and at 26 weeks with the lowest dose (200 μg). The authors suggest a low dose of folic acid fortification would be sufficient for reducing population-wide levels of homocysteine, and that higher doses would not confer a greater benefit as they do not result in significantly lower levels of homocysteine than the low dose.
Comment: In an accompanying editorial, Dr. Verhoef identifies important questions for policy makers regarding mandatory folic acid fortification. Should we expose entire populations to a compound that may prevent a relatively rare but serious developmental condition in infants? Would we be justified in accepting the risks associated with folic acid fortification even if there is some benefit to segments of the population? Should the level of fortification be lowered, and what would be the lowest effective dose? The findings that lower doses of folic acid are as effective for some outcomes as higher doses over the long term is a central consideration with respect to fortifying staple foods that, by definition, are consumed regularly throughout the lifetime.
Comment: Verhoef P. New insights on the lowest dose for mandatory folic acid fortification? Am J Clin Nutr 2011; 93:1–2.
PREDICTORS OF VITAMIN D STATUS IN THE OBESE
Lagunova Z, Porojnicu AC, Vieth R, Lindberg FA, Hexeberg S, and Moan J. Serum 25-hydroxyvitamin D is a predictor of serum 1,25-dihydroxyvitamin D in overweight and obese patients. J Nutr 2011;141:112–117.
Serum 25-hydroxyvitamin D [25(OH)D] is the precursor to the hormonally active form of vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D] and the more commonly used biomarker for vitamin D status. 1,25(OH)2D is found in much smaller concentrations than 25(OH)D, and it is more difficult to precisely measure. Recent work indicates that 1,25(OH)2D may be a more sensitive measure of vitamin D status with respect to calcium absorption, and decreased levels of 1,25(OH)2D are seen in overweight and obese individuals. The newly reported observational study by Lagunova et al. examined the predictors of 1,25(OH)2D and 25(OH)D concentrations in overweight and obese individuals.
Data on serum 1,25(OH)2D and 25(OH)D concentrations were obtained from 1,779 patients registered in a Metabolic and Medical Lifestyle Management Clinic in Oslo, Norway. Data were also obtained on body mass index (BMI), season of measurement, sex, and age. The database for the present analysis contained all observations from the clinic measuring vitamin D levels in patients between 2001 and 2007. Serum concentrations of 25(OH)D were relatively high (72.3 nmol/L), with vitamin D sufficiency defined as ≥75 nmol/L. Mean concentrations of 1,25(OH)2D were within the normal range (mean, 106.1 pmol/L; normal range, 47–163 pmol/L). Serum 25(OH)D was the strongest predictor of 1,25(OH)2D concentrations, with body composition and season of measurement also predicting 1,25(OH)2D concentrations. In this study, for each 1 kg/m2 increase in BMI, 1,25(OH)2D concentrations decreased by 0.8 pmol/L and 25(OH)D concentrations decreased by 1.3 pmol/L. Overweight and obese individuals may show reduced circulating vitamin D levels as vitamin D becomes sequestered in adipose tissue. However, overweight and obese individuals may also have lower levels of outdoor physical activity and sun exposure, and may have different dietary intake patterns than lean counterparts. The authors suggest that supplementation with vitamin D and sun exposure would benefit overweight and obese individuals, who may be at risk for vitamin D insufficiency.
HIGH-GLYCEMIC DIETS NOT ASSOCIATED WITH PROSTATE CANCER RISK
Nimptsch K, Kenfield S, Jensen MK, Stampfer MJ, Franz M, Sampson L, Brand-Miller JC, Willett WC, and Giovannucci E. Dietary glycemic index, glycemic load, insulin index, fiber and whole-grain intake in relation to risk of prostate cancer. Cancer Causes Control. 2011;22:51–61.
Over the past century, rates of prostate cancer have risen significantly in Western countries. It is hypothesized that the increased risk for prostate cancer is related to perturbations in insulin metabolism, which are related to the so-called “Western diet.” Circulating insulin may contribute to prostate cancer by inhibiting tumor cell death and promoting tumor cell proliferation, or via alterations in sex hormone metabolism. Circulating insulin and glucose handling can be negatively affected by the consumption of diets that are high in refined carbohydrates, high in glycemic load, and low in fiber. High-glycemic foods, such as white bread, white potatoes, and high-sugar foods, have a relatively large effect on postprandial blood glucose levels. A criticism of focusing on the glycemic index, however, is that foods are not generally eaten alone; rather, they are consumed as part of a meal that contains fats and proteins, which moderates the impact of a high-glycemic-index (GI) food on postprandial glucose levels. In answer to this problem, estimates of glycemic load (GL), which accounts for all components of a meal, and estimates of a food-insulin index (II), which quantifies the insulin response to foods, have been proposed. Nimptsch et al. propose that diets that are characterized by high intakes of rapidly absorbed carbohydrate and low intakes of fiber (high GI/GL) are associated with greater risk for prostate cancer. In addition, they employed the newly developed II to determine whether diets that increase insulin demand affect risk for prostate cancer.
The newly reported study represents an analysis of a subset of data available from the Health Professionals Follow-up Study (HPFS). The HPFS is an ongoing cohort study investigating the causes of chronic disease; its participant population includes 51,529 male health professionals aged between 40 and 75 years at enrollment. The study began in 1986, and participants are given health and lifestyle related questionnaires biannually. Dietary food intake was estimated using food frequency questionnaires, and GI values were assigned to foods using published values or from direct food testing. The GL of the diet over the past year was estimated by multiplying the carbohydrate content of each food by its GI, multiplying by consumption frequency, and summing for all reported food items. Values for II were obtained through food testing and represent the incremental insulin area under the curve (AUC) over 2 hours following ingestion of 1,000 kJ of the test food divided by the AUC over 2 hours following ingestion of a reference food (1,000 kJ of glucose). The primary outcome measure was incident prostate cancer.
Between baseline in 1986 and January 2007, 5,112 cases of prostate cancer were identified. Dietary GL, GI, II, or fiber intakes were not related with risk for developing prostate cancer. There was a weak association between dietary GI and low-grade prostate cancer (Gleason sum <7). The authors conclude that the findings of the present study do not support the notion that high GI/GL/II diets are related to the risk of prostate cancer.
GENE-NUTRIENT LINK BETWEEN LOW INTAKE OF POLYUNSATURATED FATTY ACIDS AND OBESITY
Junyent M, Parnell LD, Lai CQ, Arnett DK, Tsai MY, Kabagambe EK, Straka RJ, Province M, An P, Smith CE, Lee YC, Borecki I, and Ordovás JM. ADAM17_i33708A>G polymorphism interacts with dietary n-6 polyunsaturated fatty acids to modulate obesity risk in the Genetics of Lipid Lowering Drugs and Diet Network study. Nutr Metab Cardiovasc Dis. 2010;20:698–705.
Genetic factors contribute 40–70% to the susceptibility variation in obesity. Numerous genome-wide studies have identified several candidate genes associated with the risk for obesity. Importantly, considerable research shows that although specific gene variants are associated with the risk for developing obesity, environmental factors, such as physical activity, can moderate genetic risk. Such gene-environment interactions are becoming more important in our understanding of the ontology of obesity and related illnesses. The disintegrin and metalloproteinase gene ADAM17 is expressed in adipocytes, and increased levels are linked with diabetes, cardiovascular disease, obesity, and insulin resistance. ADAM17, also known as tumor necrosis factor-alpha converting enzyme (TACE), releases tumor necrosis factor (TNF), transforming growth factor-α (TNF- α), and preadipocyte factor 1 (Pref-1). ADAM17 and TNF- α are overexpressed in adipose tissue and may contribute to the development of obesity and obesity's negative sequelae. The recently reported study by Junyent et al. investigated the role of novel polymorphisms in the ADAM17gene in body composition as well as whether dietary intake of fatty acids moderated the impact of these polymorphisms on obesity.
Participants (N = 936) were enrolled in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and measures of body composition, anthropometrics, and blood pressure were taken at baseline. Dietary intake was estimated using the National Cancer Institute's Diet History Questionnaire. Blood samples were collected for genetic analysis as well as to measure fasting blood glucose, blood lipids, insulin, and adiponectin levels. Six ADAM17 single nucleotide polymorphisms (SNPs), m1254A>G, i14121C>A, i33708A>G, i48827A>C, i53440C>T, and i62781G>T, were genotyped. Individuals with the ADAM17_ m1254A>G polymorphism (AG or AG) had a significantly higher risk of obesity, higher insulin levels, and lower HDL-C concentrations than those with the AA variant. These factors were not modified further by diet. Individuals with the AA variant of the ADAM17_i33708A>G SNP had a greater risk for obesity, were heavier, and had higher BMIs and waist circumferences than those with the GG variant. In individuals with the AA variant, low dietary intakes of n-6 polyunsaturated fatty acids (PUFA) were associated with increased risk of obesity, but those with high intakes of PUFA showed no differences in risk for obesity when compared with the GG phenotype. The authors indicate that interpretation of the data from this study should be tempered by the limitations of the study, namely, its cross-sectional design, the primarily white study population, and the short follow-up time. Nevertheless, the data from the present study highlight a need to identify gene-diet interactions that can have practical applications in the treatment or prevention of obesity.