Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

Cardiometabolic Risk Factors at 5 Years After Omega-3 Fatty Acid Supplementation in Infancy.

BACKGROUND: Omega-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation during infancy may reduce adult cardiovascular risk as observed in animals. We assessed the effect of n-3 LCPUFA supplementation in infancy on growth, body composition, and cardiometabolic risk factors at 5 years of age. METHODS: Infants were randomly assigned to a daily supplement of n-3 LCPUFA or olive oil (control) from birth to 6 months (n = 420). Measurements included weight, length, cord blood adipokines at birth and anthropometry, skinfolds, blood pressure, heart rate, fasting blood adipokines, and biochemistry at 5 years. RESULTS: The infants who received n-3 LCPUFA had a smaller waist circumference at 5 years (coefficient: 1.1 cm; 95% confidence interval [CI]: 0.01 to 2.14), which remained significant after adjustments for confounders (coefficient: 0.8 cm; 95% CI: 0.19 to 1.30). Five-year-old boys who received n-3 LCPUFA supplementation as infants had a 21% reduction in insulin concentrations (ratio: 0.79; 95% CI: 0.66 to 0.94) and a 22% reduction in insulin resistance (ratio: 0.78; 95% CI: 0.64 to 0.95) compared with the control group. There were no other differences in growth and cardiometabolic risk factors between the groups for the whole cohort at birth, 2.5, or 5 years. CONCLUSIONS: Supplementation with n-3 LCPUFA in infancy revealed a reduction in waist circumference at 5 years. Boys in the n-3 LCPUFA group showed reduced insulin concentrations and insulin resistance at 5 years, which may have beneficial outcomes for later health. No effects were seen in girls. Longer term follow-up of the cohort is warranted to determine whether these differences are maintained into adolescence.

Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: a double-blind, randomised controlled clinical trial.

Resolution of inflammation is an active process involving specialised pro-resolving mediators (SPM) generated from the n-3 fatty acids EPA and DHA. n-3 Fatty acid supplementation during pregnancy may provide an intervention strategy to modify these novel SPM. This study aimed to assess the effect of n-3 fatty acid supplementation in pregnancy on offspring SPM at birth and 12 years of age (12 years). In all, ninety-eight atopic pregnant women were randomised to 3·7 g daily n-3 fatty acids or a control (olive oil), from 20 weeks gestation until delivery. Blood was collected from the offspring at birth and at 12 years. Plasma SPM consisting of 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins, 17-hydroxydocosahexaenoic acid (17-HDHA), D-series resolvins, 14-hydroxydocosahexaenoic acid (14-HDHA), 10 S,17S-dihydroxydocosahexaenoic acid, maresins and protectin 1, were measured by liquid chromatography-tandem MS. We identified the resolvins RvE1, RvE2, RvE3, RvD1, 17R-RvD1 and RvD2 for the first time in human cord blood. n-3 Fatty acids increased cord blood 18-HEPE (P<0·001) derived from EPA relative to the control group. DHA-derived 17-HDHA at birth was significantly increased in the n-3 fatty acid group relative to the controls (P=0·001), but other SPM were not different between the groups. n-3 Fatty acid supplementation during pregnancy was associated with an increase in SPM precursors in the offspring at birth but the effects were not sustained at 12 years. The presence of these SPM, particularly at birth, may have functions relevant in the newborn that remain to be established, which may be useful for future investigations.

Serum 25-hydroxyvitamin D concentrations and cardiometabolic risk factors in adolescents and young adults.

Evidence associating serum 25-hydroxyvitamin D (25(OH)D) concentrations and cardiometabolic risk factors is inconsistent and studies have largely been conducted in adult populations. We examined the prospective associations between serum 25(OH)D concentrations and cardiometabolic risk factors from adolescence to young adulthood in the West Australian Pregnancy Cohort (Raine) Study. Serum 25(OH)D concentrations, BMI, homoeostasis model assessment for insulin resistance (HOMA-IR), TAG, HDL-cholesterol and systolic blood pressure (SBP) were measured at the 17-year (n 1015) and 20-year (n 1117) follow-ups. Hierarchical linear mixed models with maximum likelihood estimation were used to investigate associations between serum 25(OH)D concentrations and cardiometabolic risk factors, accounting for potential confounders. In males and females, respectively, mean serum 25(OH)D concentrations were 73·6 (sd 28·2) and 75·4 (sd 25·9) nmol/l at 17 years and 70·0 (sd 24·2) and 74·3 (sd 26·2) nmol/l at 20 years. Deseasonalised serum 25(OH)D3 concentrations were inversely associated with BMI (coefficient -0·01; 95 % CI -0·03, -0·003; P=0·014). No change over time was detected in the association for males; for females, the inverse association was stronger at 20 years compared with 17 years. Serum 25(OH)D concentrations were inversely associated with log-HOMA-IR (coefficient -0·002; 95 % CI -0·003, -0·001; P<0·001) and positively associated with log-TAG in females (coefficient 0·002; 95 % CI 0·0008, 0·004; P=0·003). These associations did not vary over time. There were no significant associations between serum 25(OH)D concentrations and HDL-cholesterol or SBP. Clinical trials in those with insufficient vitamin D status may be warranted to determine any beneficial effect of vitamin D supplementation on insulin resistance, while monitoring for any deleterious effect on TAG.

n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease.

DNA telomere shortening associates with the age-related increase cardiovascular disease (CVD) risk. Reducing oxidative stress, could modify telomere erosion during cell replication, and CVD risk in patients with chronic kidney disease (CKD). The effect of n-3 fatty acids and coenzyme Q10 (CoQ) on telomere length was studied in a double-blind placebo-controlled trial in CKD. Eighty-five CKD patients were randomized to: n-3 fatty acids (4 g); CoQ (200 mg); both supplements; or control (4 g olive oil), daily for 8 weeks. Telomere length was measured in neutrophils and peripheral blood mononuclear cells (PBMC) at baseline and 8 weeks, with and without correction for cell counts. Main and interactive effects of n-3 fatty acids and CoQ on telomere length were assessed adjusting for baseline values. F2-isoprostanes were measured as markers of oxidative stress. There was no effect of n-3 fatty acids or CoQ on neutrophil or PBMC telomere length. However, telomere length corrected for neutrophil count was increased after n-3 fatty acids (p = 0.015). Post-intervention plasma F2-isoprostanes were negative predictors of post-intervention telomere length corrected for neutrophil count (p = 0.025).The effect of n-3 fatty acids to increased telomere length corrected for neutrophil count may relate to reduced oxidative stress and increased clearance of neutrophils with shorter telomeres from the circulation. This may be a novel mechanism of modifying CVD risk in CKD patients.

A randomized controlled trial of the effects of n-3 fatty acids on resolvins in chronic kidney disease.

BACKGROUND AND OBJECTIVE: The high incidence of cardiovascular disease (CVD) in chronic kidney disease (CKD) is related partially to chronic inflammation. n-3 Fatty acids have been shown to have anti-inflammatory effects and to reduce the risk of CVD. Specialized Proresolving Lipid Mediators (SPMs) derived from the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) actively promote the resolution of inflammation. This study evaluates the effects of n-3 fatty acid supplementation on plasma SPMs in patients with CKD. METHODS: In a double-blind, placebo-controlled intervention of factorial design, 85 patients were randomized to either n-3 fatty acids (4 g), Coenzyme Q10 (CoQ) (200 mg), both supplements, or control (4 g olive oil), daily for 8 weeks. The SPMs 18-HEPE, 17-HDHA, RvD1, 17R-RvD1, and RvD2, were measured in plasma by liquid chromatography-tandem mass spectrometry before and after intervention. RESULTS: Seventy four patients completed the 8 weeks intervention. n-3 Fatty acids but not CoQ significantly increased (P < 0.0001) plasma levels of 18-HEPE and 17-HDHA, the upstream precursors to the E- and D-series resolvins, respectively. RvD1 was significantly increased (P = 0.036) after n-3 fatty acids, but no change was seen in other SPMs. In regression analysis the increase in 18-HEPE and 17-HDHA after n-3 fatty acids was significantly predicted by the change in platelet EPA and DHA, respectively. CONCLUSION: SPMs are increased after 8 weeks n-3 fatty acid supplementation in patients with CKD. This may have important implications for limiting ongoing low grade inflammation in CKD.

Nutritional influences on epigenetic programming: asthma, allergy, and obesity.

Observational studies show consistent links between early-life nutritional exposures as important risk factors for the development of asthma, allergy, and obesity. Reliance on increasing use of dietary supplementation and fortification (eg, with folate) to compensate for increased consumption of processed foods is also influencing immune and metabolic outcomes. Epigenetics is providing substantial advances in understanding how early-life nutritional exposures can effect disease development. This article summarizes current evidence linking the influence of early-life nutritional exposures on epigenetic regulation with a focus on the disease outcomes of asthma, allergy, and obesity.

Supplementation with N-3 long-chain polyunsaturated fatty acids or olive oil in men and women with renal disease induces differential changes in the DNA methylation of FADS2 and ELOVL5 in peripheral blood mononuclear cells.

BACKGROUND: Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid supplementation on the epigenetic regulation of genes in adult humans. METHODS AND RESULTS: We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5' regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts. CONCLUSIONS: These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function.

Low serum 25-hydroxyvitamin D concentrations associate with non-alcoholic fatty liver disease in adolescents independent of adiposity.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and serum 25-hydroxyvitamin D (s25[OH]D) concentrations are both associated with adiposity and insulin resistance (IR) and thus may be pathogenically linked. We aimed to determine the prevalence of vitamin D deficiency in adolescents with NAFLD and to investigate the prospective and cross-sectional associations between s25[OH]D concentrations and NAFLD. METHODS: Participants in the population-based West Australian Pregnancy (Raine) Cohort had seasonally adjusted s25(OH)D concentrations determined at ages 14 and then 17 years. NAFLD was diagnosed at 17 years using liver ultrasonography. Associations were examined after adjusting for potential confounders. Odds ratios (ORs) and confidence intervals (CIs) are reported per standard deviation in s25(OH)D concentrations. RESULTS: NAFLD was present in 16% (156/994) of adolescents. The majority of participants with NAFLD had either insufficient (51%) or deficient (17%) vitamin D status. s25(OH)D concentrations at 17 years were inversely associated with risk of NAFLD (OR 0.74, 95% CI 0.56, 0.97; P = 0.029), after adjusting for sex, race, physical activity, television/computer viewing, body mass index, and IR. The effect of s25(OH)D concentrations at 17 years was minimally affected after further adjusting for s25(OH)D concentrations at 14 years (OR 0.76, 95% CI 0.56, 1.03; P = 0.072). CONCLUSIONS: Lower s25(OH)D concentrations are significantly associated with NAFLD, independent of adiposity and IR. Screening for vitamin D deficiency in adolescents at risk of NAFLD is appropriate, and clinical trials investigating the effect of vitamin D supplementation in the prevention and treatment of NAFLD may be warranted.