Dietary ω-3 fatty acids and the incidence of atrial fibrillation in the Million Veteran Program.

BACKGROUND: Although recent large randomized clinical trials have reported an increased risk of atrial fibrillation (AF) with marine ω-3 fatty acid supplements, it is unclear whether dietary marine ω-3 fatty acids assessed through food frequency questionnaires are associated with AF risk. OBJECTIVES: We sought to test the hypothesis that dietary eicosapentaenoic acid/docosahexaenoic acid/docosapentaecnoic acid (EPA/DHA/DPA) is associated with a higher risk of AF in a large prospective cohort of US Veterans. METHODS: We analyzed data from Million Veteran Program participants who completed self-reported food frequency questionnaires. We used multivariable Cox regression to estimate the HRs of AF across quintiles of ω-3 fatty acid consumption and a cubic spline analysis to assess the dose-response relations between ω-3 fatty acids and AF. RESULTS: Of the 301,294 veterans studied, the median intake of ω-3 fatty acids (EPA/DHA/DPA) was 219 mg/d (IQR: 144-575), and the mean age was 64.9 y (SD: 12.0); 91% were men, and 84% were White. Consumption of EPA/DHA/DPA exhibited a nonlinear inverse relation with incident AF characterized by an initial decline to 11% at 750 mg/d of marine ω-3 fatty acid intake followed by a plateau. CONCLUSIONS: Contrary to our hypothesis, dietary EPA/DHA/DPA was not associated with a higher risk of AF but was inversely related to AF risk in a nonlinear manner.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Omega-3 supplement use, fish intake, and risk of non-fatal coronary artery disease and ischemic stroke in the Million Veteran Program.

BACKGROUND & AIMS: Observational and clinical trial evidence suggests an inverse association of omega-3 polyunsaturated fatty acids with coronary artery disease (CAD) mortality, although relationships with non-fatal CAD and stroke are less clear. We investigated whether omega-3 fatty acid supplement use and fish intake were associated with incident non-fatal CAD and ischemic stroke among US Veterans. METHODS: The Million Veteran Program (MVP) is an ongoing nation-wide longitudinal cohort study of US Veterans with self-reported survey, biospecimen, and electronic health record data. Regular use of omega-3 supplements (yes/no) and frequency of fish intake within the past year were assessed using a food frequency questionnaire. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of omega-3 supplement use and fish intake with incident non-fatal CAD and ischemic stroke, defined from electronic health records using validated algorithms. Multivariable models included demographics, body mass index, education, smoking status, alcohol intake, and exercise frequency. RESULTS: Among 197,761 participants with food frequency data (mean age: 66 ± 12 years, 92% men), 21% regularly took omega-3 supplements and median fish intake was 1 (3-5 ounce) serving/week. Over a median follow-up of 2.9 years for non-fatal CAD and 3.3 years for non-fatal ischemic stroke, we observed 6265 and 4042 incident cases of non-fatal CAD and non-fatal ischemic stroke, respectively. Omega-3 fatty acid supplement use was independently associated with a lower risk of non-fatal ischemic stroke [HR (95% CI): 0.88 (0.81, 0.95)] but not non-fatal CAD [0.99 (0.93, 1.06)]. Fish intake was not independently associated with non-fatal CAD [1.01 (0.94, 1.09) for 1-3 servings/month, 1.03 (0.98, 1.11) for 1 serving/week, 1.02 (0.93, 1.11) for 2-4 servings/week, and 1.15 (0.98, 1.35) for ≥5 servings/week, reference = <1 serving/month, linear p-trend = 0.09] or non-fatal ischemic stroke [0.92 (0.84, 1.00) for 1-3 servings/month, 0.93 (0.85, 1.02) for 1 serving/week, 0.96 (0.86, 1.07) for 2-4 servings/week, and 1.13 (0.93-1.38) for ≥5 servings/week, linear p-trend = 0.16]. CONCLUSIONS: Neither omega-3 supplement use, nor fish intake, was associated with non-fatal CAD among US Veterans. While omega-3 supplement use was associated with lower risk of non-fatal ischemic stroke, fish intake was not. Randomized controlled trials are needed to confirm whether omega-3 supplementation is protective against ischemic stroke in a US population.

Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association.

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.

Optimal vitamin D status attenuates the age-associated increase in systolic blood pressure in white Americans: results from the third National Health and Nutrition Examination Survey.

BACKGROUND: The prevalences of both hypertension and vitamin D insufficiency are high in the United States. Recent clinical trials and animal studies have suggested that vitamin D insufficiency may be associated with elevated blood pressure. OBJECTIVE: With cross-sectional data, we sought to determine whether vitamin D concentrations were related to systolic blood pressure (SBP) in the third National Health and Nutrition Examination Survey (1988-1992). DESIGN: Blood pressure was classified with 5 categories from the Joint National Committee 7 with a sixth category added to distinguish participants with normotensive SBP (<110 mm Hg) from those with high-normal SBP (110-119 mm Hg). We used predicted marginals to estimate the conditional means of serum 25 hydroxyvitamin D [25(OH)D] and to test for trend across blood pressure categories. We used linear regression to explore the association between vitamin D, blood pressure, and age. RESULTS: Lower 25(OH)D concentrations were associated with a higher blood pressure category in whites (P<0.001); however, when controlling for age, the association was no longer significant. Concentrations of 25(OH)D>80 nmol/L decreased the age-related increase in SBP by 20% compared with participants having 25(OH)D concentrations<50 nmol/L (P<0.001). Only 8% of blacks had 25(OH)D concentrations>80 nmol/L. CONCLUSIONS: SBP is inversely associated with serum vitamin D concentrations in nonhypertensive white persons in the United States. This observation provides a rationale for studies on the potential effects of vitamin D supplementation as a method to reduce SBP in persons at risk of hypertension.

Vitamin K intake and bone mineral density in women and men.

BACKGROUND: Low dietary vitamin K intake has been associated with an increased risk of hip fracture in men and women. Few data exist on the association between dietary vitamin K intake and bone mineral density (BMD). OBJECTIVE: We studied cross-sectional associations between self-reported dietary vitamin K intake and BMD of the hip and spine in men and women aged 29-86 y. DESIGN: BMD was measured at the hip and spine in 1112 men and 1479 women (macro x +/- SD age: 59 +/- 9 y) who participated in the Framingham Heart Study (1996-2000). Dietary and supplemental intakes of vitamin K were assessed with the use of a food-frequency questionnaire. Additional covariates included age, body mass index, smoking status, alcohol use, physical activity score, and menopause status and current estrogen use among the women. RESULTS: Women in the lowest quartile of vitamin K intake (macro x: 70.2 microg/d) had significantly (P < or = 0.005) lower mean (+/- SEM) BMD at the femoral neck (0.854 +/- 0.006 g/cm(2)) and spine (1.140 +/- 0.010 g/cm(2)) than did those in the highest quartile of vitamin K intake (macro x: 309 microg/d): 0.888 +/- 0.006 and 1.190 +/- 0.010 g/cm(2), respectively. These associations remained after potential confounders were controlled for and after stratification by age or supplement use. No significant association was found between dietary vitamin K intake and BMD in men. CONCLUSIONS: Low dietary vitamin K intake was associated with low BMD in women, consistent with previous reports that low dietary vitamin K intake is associated with an increased risk of hip fracture. In contrast, there was no association between dietary vitamin K intake and BMD in men.

Dietary factors associated with the risk of high iron stores in the elderly Framingham Heart Study cohort.

BACKGROUND: High body iron stores may increase the risk of several chronic diseases. Whether dietary factors contribute to the risk of high iron stores is unknown. OBJECTIVE: We assessed the relation between dietary factors and the risk of high iron stores in the elderly Framingham Heart Study cohort. DESIGN: We examined the relation between the usual intake of dietary factors (food-frequency questionnaire) and the risk of high iron stores (serum ferritin >300 and 200 micro g/L in men and women, respectively) in 614 subjects aged 68-93 y. RESULTS: The risk of high iron stores was significantly higher 1) in subjects who took > or =30 mg supplemental Fe/d than in nonusers [odds ratio (OR): 4.32; 95% CI: 1.63, 11.47], 2) in subjects who consumed >21 servings of fruit/wk than in those who consumed < or =14 servings/wk (OR: 2.88; 95% CI: 1.26, 6.61), and 3) in subjects who consumed >4 but <7 or > or=7 servings of red meat/wk than in those who consumed < or =4 servings/wk (ORs: 2.94 and 3.61, respectively; 95% CIs: 1.33, 6.47 and 1.57, 8.27, respectively). Whole-grain intake (>7 servings/wk) was inversely associated (OR: 0.23; 95% CI: 0.07, 0.75). CONCLUSIONS: Among elders, intakes of highly bioavailable forms of iron (supplemental iron and red meat) and of fruit, a dietary source of an enhancer of nonheme-iron absorption (vitamin C), promote high iron stores, whereas foods containing phytate (whole grains) decrease these stores. Individual dietary patterns may be important modulators of high iron stores.

Folic acid intake from fortification in United States exceeds predictions.

In 1996, the U.S. Food and Drug Administration issued a regulation requiring that all enriched cereal-grain products be fortified with folic acid by January 1998. An average increase in folic acid intake of 100 micro g/d was projected as a result of this fortification. The objective of the present study was to estimate the effect of this fortification on the intake of folic acid and total folate, and on the prevalence of individuals with inadequate folate intake and with high folic acid intake. We used data on food and nutrient intake from 1480 individuals who participated in the 5th and 6th examinations of the Framingham Offspring Cohort Study. Fortification was instituted during the 6th examination so that 931 participants were examined before its implementation (nonexposed) and 549 after implementation (exposed). Published data on total folate in enriched cereal-grain products were used to correct folate content in these foods to reflect fortification. Among nonsupplement users, folic acid intake increased by a mean of 190 [95% confidence interval (CI): 176, 204] micro g/d (P < 0.001) and total folate intake increased by a mean of 323 (95% CI: 296-350) micro g dietary folate equivalents (DFE)/d (P < 0.001) in the exposed participants. Similar increases were seen among supplement users exposed to fortification. The prevalence of exposed individuals with total folate intake below the estimated average requirement (320 micro g DFE/d) decreased from 48.6% (95% CI: 44.2-53.1%) before fortification to 7.0% (95% CI: 3.1-10.9%) after fortification in individuals who did not use folic acid supplements. This prevalence was approximately 1% or less for users of supplements both before and after fortification. Prevalence of individuals with folic acid intake above the upper tolerable intake level (1000 micro g folic acid/d) increased only among supplement users exposed to fortification (from 1.3 to 11.3%, P < 0.001). No changes in folic acid intake were observed over time in the nonexposed participants. By these estimations, folic acid fortification resulted in a mean increase in folic acid intake that was approximately twice as large as previously projected.

Obesity, diabetes, and risk of cardiovascular disease in the elderly.

There is an age-related increase in total body fat and visceral adiposity until age 65 years that often is accompanied by diabetes or impaired glucose tolerance. The prevalence of type 2 diabetes increases progressively with age, peaking at 16.5% in men and 12.8% in women at age 75-84 years. Over age 65, diabetes or glucose intolerance was present in 30%-40% of Framingham Study subjects. There has been an alarming increase, of epidemic proportions, in both obesity and diabetes in the general population. Type 2 diabetes and obesity are both associated with a clustering of atherogenic risk factors, and when three or more are present it generally signifies an insulin resistance syndrome. This is promoted by weight gain and visceral adiposity. The risk of macrovascular disease is increased before glucose levels reach the diagnostic threshold for "diabetes," and 25% of newly diagnosed diabetics already have overt cardiovascular disease. In the Framingham Study, increased risk of cardiovascular disease was two-fold in men and three-fold in women, eliminating the female advantage over men for all outcomes except stroke. Coronary disease is the most common and lethal sequela, and unrecognized myocardial infarctions are three times more common in diabetic than nondiabetic men. Following a myocardial infarction, diabetes imposes a high rate of recurrence, heart failure, and death, more so in women than men. The risk of cardiovascular sequelae in diabetics is variable, the majority of events occurring in those with two or more additional risk factors. Because of the variable risk of cardiovascular disease in either the diabetic or obese person, risk stratification is necessary to determine the hazard of impending cardiovascular disease. This is readily accomplished with Framingham cardiovascular risk formulations. For persons with diabetes or obesity, the chief goal is to avoid the common cardiovascular sequelae. Comprehensive care should include not only normalization of the blood sugar, but also weight reduction, dietary fat restriction, strict blood pressure and lipid control, exercise, and avoidance of tobacco. Trial data indicate that preventive measures benefit obese diabetics even more than nondiabetics.

Dietary intake of phytoestrogens is associated with a favorable metabolic cardiovascular risk profile in postmenopausal U.S.women: the Framingham study.

Hypertension, central obesity and dyslipidemia are associated with high cardiovascular risk. Estrogen therapy in women has beneficial effects on some of these metabolic cardiovascular risk factors. It is not known whether dietary estrogens have similar effects, especially in Western populations. We studied the association between dietary phytoestrogen intake and metabolic cardiovascular risk factors in postmenopausal women. For this purpose, 939 postmenopausal women participating in the Framingham Offspring Study were included in this cross-sectional study. Mean blood pressure, waist-hip ratio (WHR) and lipoprotein levels were determined in quartile categories of dietary phytoestrogen (isoflavones and lignans) intake, determined by a food-frequency questionnaire. In addition, a metabolic syndrome score was defined according to WHO criteria (range 0-6). The WHR was lower in women in the highest quartile of intake of lignans compared with the lowest [-0.017; 95% confidence interval (CI) -0.030 to -0.0016]. In the highest quartile of intake of isoflavones, plasma triglyceride levels were 0.16 mmol/L lower (95% CI, -0.30 to -0.02) compared with the lowest quartile of isoflavones; for lignan intake, this difference was 0.23 mmol/L (95% CI, -0.37 to -0.09). In the highest quartile of isoflavone intake, the mean cardiovascular risk factor metabolic score was 0.43 points lower (95% CI, -0.70 to -0.16) than the lowest quartile. The difference in this score between the extreme quartiles of intake of lignans was -0.55 points (95% CI, -0.82 to -0.28). In conclusion, high intake of phytoestrogens in postmenopausal women appears to be associated with a favorable metabolic cardiovascular risk profile.

Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner: the Framingham Study.

BACKGROUND: A common G-to-A substitution in the promoter area (-75 base pairs) of the apolipoprotein A-I gene (APOA1) has been described. The A allele was shown to be associated with higher HDL-cholesterol concentrations in some studies but not in others. OBJECTIVE: We examined whether dietary fat modulates the association between this polymorphism and HDL-cholesterol concentrations. DESIGN: We studied a population-based sample of 755 men and 822 women from the Framingham Offspring Study. RESULTS: The frequency of the A allele was 0.165. No significant differences were observed between G/G subjects and carriers of the A allele for any lipid variables. In multivariate linear regression models, HDL-cholesterol concentrations in women were associated with a significant interaction between polyunsaturated fatty acid (PUFA) intake as a continuous variable and APOA1 genotype (P = 0.005). By using 3 categories of PUFA intake, we found a significantly different effect of APOA1 genotype across PUFA categories in women. When PUFA intake was <4% of energy, G/G subjects had approximately 14% higher HDL-cholesterol concentrations than did carriers of the A allele (P < 0.05). Conversely, when PUFA intake was >8%, HDL-cholesterol concentrations in carriers of the A allele were 13% higher than those of G/G subjects (P < 0.05). No significant allelic difference was observed for subjects in the range of PUFA intake of 4-8% of energy. These interactions were not significant in men. CONCLUSIONS: We found a significant gene-diet interaction associated with the APOA1 G-A polymorphism. In women carriers of the A allele, higher PUFA intakes were associated with higher HDL-cholesterol concentrations, whereas the opposite effect was observed in G/G women.