The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Indicators of Self-Determination in Therapeutic Songwriting Lyrics Created by Adults with High LDL Cholesterol.

Individuals with low-density lipoprotein cholesterol ≥190 mg/dL are at high risk for atherosclerotic cardiovascular disease events. Our goal was to determine if adults with this condition would express important psychological, health, and motivation themes when generating lyrics during music therapy. Thirty-one participants each created their own original song with the help of a music therapist. The lyrics were analyzed using a deductive approach guided by Self-Determination Theory (specifically the satisfaction or frustration of basic psychological needs): (1) for each entire song (macro-analysis) and (2) line-by-line (micro-analysis). Song lyrics generated during music therapy sessions by patients with a low-density lipoprotein cholesterol ≥190 mg/dL revealed the presence of the three basic needs (autonomy, competence, and relatedness) of Self-Determination Theory. The most prevalent theme identified in the macro-analysis of songs was autonomy satisfaction, coded in 25 songs (27.17% of all macro codes), and followed by competence satisfaction in 17 songs (18.48%) and relatedness satisfaction in 15 songs (16.3%). Line-by-line micro-analysis of lyrics revealed that at least one basic need of Self-Determination Theory was present in 277 of the unique lyric lines (50%); 107 (19%) for relatedness, 101 (18%) for autonomy, and 69 (13%) for competence. Need satisfaction occurred more frequently than need frustration in both analyses. However, depending on the level of analysis (macro or micro), results differed as to which themes were most prevalent. These results indicate that therapeutic songwriting may be a unique way to identify the basic psychological needs that, when satisfied, indicate self-determination.

Aspirin and omega-3 polyunsaturated fatty acid use and their interaction in cardiovascular diseases and colorectal adenomas.

Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA-resistant or diabetic patients. EPA- and DHA-deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are 'V-shaped' such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location- and subtype-specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however, ultra-low doses (30 mg/d) can also reduce thrombosis. EPA-to-DHA ratio is also important with regard to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation; however, high-dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.

Aspirin and omega-3 fatty acid status interact in the prevention of cardiovascular diseases in Framingham Heart Study.

BACKGROUND: The roles of omega-3 (n3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and low-dose aspirin in the primary prevention of ischemic cardiovascular disease (CVD) are controversial. Since omega-3 (n3) fatty acids and aspirin affect cyclooxygenase activity in platelets, there could be a clinically-relevant effect of aspirin combined with a particular n3 fatty acid level present in each individual. METHODS: RBC EPA+DHA, arachidonic acid (AA) and docosapentaenoic acid (DPA) were measured in 2500 participants without known CVD in the Framingham Heart Study. We then tested for interactions with reported aspirin use (1004 reported use and 1494 did not) on CVD outcomes. The median follow-up was 7.2 years. RESULTS: Having RBC EPA+DHA in the second quintile (4.2-4.9% of total fatty acids) was associated with significantly reduced risk for future CVD events (relative to the first quintile, <4.2%) in those who did not take aspirin (HR 0.54 (0.30, 0.98)), but in those reporting aspirin use, risk was significantly increased (HR 2.16 (1.19, 3.92)) in this quintile. This interaction remained significant when adjusting for confounders. Significant interactions were also present for coronary heart disease and stroke outcomes using the same quintiles. Similar findings were present for EPA and DHA alone but not for DPA and AA. CONCLUSIONS: There is a complex interaction between aspirin use and RBC EPA+DHA levels on CVD outcomes. This suggests that aspirin use may be beneficial in one omega-3 environment but harmful in another, implying that a personalized approach to both aspirin use and omega-3 supplementation may be needed.

The effects of aspirin and N-3 fatty acids on telomerase activity in adults with diabetes mellitus.

Type 2 Diabetes mellitus is associated with aging and shortened telomere length. Telomerase replaces lost telomeric repeats at the ends of chromosomes and is necessary for the replicative immortality of cells. Aspirin and the n3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are commonly used therapies in people with type 2 diabetes for reducing cardiovascular disease events, though their relation to telomerase activity is not well studied. We explored the effects of aspirin, EPA + DHA, and the combined effects of aspirin and EPA + DHA treatment on telomerase activity in 30 adults with diabetes mellitus. EPA and DHA ingestion alone increased telomerase activity then a decrease occurred with the addition of aspirin consumption. Crude (F-stat = 2.09, p = 0.13) and adjusted (F-stat = 2.20, p = 0.14) analyses of this decrease showed signs of a trend. These results suggest that aspirin has an adverse effect on aging in diabetics who have relatively high EPA and DHA ingestion.

Predicting Risk for Incident Heart Failure With Omega-3 Fatty Acids: From MESA.

OBJECTIVES: The aim of this study was to determine if plasma eicosapentaenoic acid (EPA) abundance (%EPA) is associated with reduced hazard for primary heart failure (HF) events in the MESA (Multi-Ethnic Study of Atherosclerosis) trial. BACKGROUND: Clinical trials suggest that omega-3 polyunsaturated fatty acids (ω3 PUFAs) prevent sudden death in coronary heart disease and HF, but this is controversial. In mice, the authors demonstrated that the ω3 PUFA EPA prevents contractile dysfunction and fibrosis in an HF model, but whether this extends to humans is unclear. METHODS: In the MESA cohort, the authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced ejection fraction (EF) (EF <45%) and HF with preserved EF (EF ≥45%) using Cox proportional hazards modeling. RESULTS: A total of 6,562 participants 45 to 84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HF with reduced EF, 110 HF with preserved EF, and 54 with unknown EF status. %EPA in HF-free participants was 0.76% (0.75% to 0.77%) but was lower in participants with HF at 0.69% (0.64% to 0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio: 0.73 [95% confidence interval: 0.60 to 0.91] per log-unit difference in %EPA; p = 0.001). Adjusting for age, sex, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. Sensitivity analyses showed no dependence on HF type. CONCLUSIONS: Higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

ω3-Polyunsaturated fatty acids for heart failure: Effects of dose on efficacy and novel signaling through free fatty acid receptor 4.

Heart failure (HF) affects 5.7 million in the U.S., and despite well-established pharmacologic therapy, the 5-year mortality rate remains near 50%. Furthermore, the mortality rate for HF has not declined in years, highlighting the need for new therapeutic options. Omega-3 polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important regulators of cardiovascular health. However, questions of efficacy and mechanism of action have made the use of ω3-PUFAs in all cardiovascular disease (CVD) controversial. Here, we review recent studies in animal models of HF indicating that ω3-PUFAs, particularly EPA, are cardioprotective, with the results indicating a threshold for efficacy. We also examine clinical studies suggesting that ω3-PUFAs improve outcomes in patients with HF. Due to the relatively small number of clinical studies of ω3-PUFAs in HF, we discuss EPA concentration-dependency on outcomes in clinical trials of CVD to gain insight into the perceived questionable efficacy of ω3-PUFAs clinically, with the results again indicating a threshold for efficacy. Ultimately, we suggest that the main failing of ω3-PUFAs in clinical trials might be a failure to reach a therapeutically effective concentration. We also examine mechanistic studies suggesting that ω3-PUFAs signal through free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor (GPR) for long-chain fatty acids (FA), thereby identifying an entirely novel mechanism of action for ω3-PUFA mediated cardioprotection. Finally, based on mechanistic animal studies suggesting that EPA prevents interstitial fibrosis and diastolic dysfunction, we speculate about a potential benefit for EPA-Ffar4 signaling in heart failure preserved with ejection fraction.

Associations between Omega-3 Index increase and triacylglyceride decrease in subjects with hypertriglyceridemia in response to six month of EPA and DHA supplementation.

INTRODUCTION: Ingestion of long-chain n-3 PUFA effectively decreases serum triacylglycerol (TAG) levels and increases the Omega-3 Index, defined as the % of EPA and DHA in erythrocyte fatty acids. However, it remains unclear whether there is a relationship between the Omega-3 Index increase (ΔO3I increase) and the TAG level decrease (ΔTAG). We hypothesized that TAG reduction is strongly depended on Omega-3 Index increase. SUBJECTS AND METHODS: Secondary analyses of data from a former double-blind placebo-controlled trial in which 150 dyslipidemic statin-treated subjects were randomized to four capsules of fish oil daily either as re-esterified TAG or ethyl esters in identical doses (1.01 g EPA+0.67 g DHA) or corn oil as a placebo for a period of six month. RESULTS: 108 subjects fulfilled the criteria of the current study protocol and were included in the analyses. A weak but significant negative correlation between ΔO3I and ΔTAG was observed (r=-0.211, p<0.05). However, the relation between ΔO3I and serum ΔTAG was not linear (coefficients of determination R(2): 0.044). After sub-grouping the study population into Omega-3 Index response groups, the group with a mean ΔO3I of>4% after six months of n-3 PUFA treatment demonstrated the greatest TAG reduction. DISCUSSION AND CONCLUSIONS: A weak association between Omega-3 Index increase and TAG level decrease was found. This may be explained by highly fluctuating TAG levels, a large inter-individual difference in response of the Omega-3 Index, a cohort of subjects with only slightly elevated TAG levels and high Omega-3 Index values at baseline, and possibly to insufficient statistical power. Since there was no strong association between Omega-3 Index increase and the TAG level decrease, we conclude that changes in serum TAG levels are not a viable substitute for the Omega-3 Index to monitor treatment with EPA and DHA.

Treatment with omega-3 fatty acid ethyl-ester alters fatty acid composition of lipoproteins in overweight or obese adults with insulin resistance.

INTRODUCTION: The effects of dietary fatty acid supplementation on lipoprotein fatty acid composition have rarely been described. PATIENTS AND METHODS: Sixty-one overweight and obese adults with dyslipidemia and insulin resistance were randomized to placebo, 2g/day extended-release nicotinic acid (ERN), 4g/day prescription omega-3 fatty acid ethyl ester (P-OM3), or combination therapy for 16 weeks. Lipoprotein fatty acid composition was analyzed by gas chromatography pre- and post-treatment. RESULTS: Treatment with P-OM3 or combination, but not ERN, increased proportions of eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid, and reduced those for arachidonic acid in all lipoprotein fractions, with greatest impact in the high-density lipoprotein fraction. P-OM3-induced changes in eicosapentaenoic acid within low-density lipoproteins and very low-density lipoproteins were associated with beneficial effects on mean arterial pressure and pulse pressure. CONCLUSIONS: P-OM3 supplementation, with or without ERN, was associated with differentially altered lipoprotein fatty acid composition and improved blood pressure parameters.

The effects of aspirin and fish oil consumption on lysophosphatidylcholines and lysophosphatidic acids and their correlates with platelet aggregation in adults with diabetes mellitus.

Many diabetics are insensitive to aspirin's platelet anti-aggregation effects. The influence of co-administration of aspirin and fish oil (FO) on plasma lysophospholipids in subjects with diabetes is poorly characterized. Thirty adults with type 2 diabetes mellitus were treated with aspirin (81mg/day) for seven days, then with FO (4g/day) for 28 days, then in combination for another seven days. Lysophospholipids and platelet measures were determined after acute (4h) and chronic (7 days) ingestion of aspirin, FO, or both in combination. FO ingestion reduced all lysophosphatidic acid (LPA) concentrations, while EPA (20:5n-3) and DHA (22:6n-3) lysophosphatidylcholine (LPC) concentrations significantly increased after FO alone and in combination with aspirin. In vitro arachidonic acid-induced platelet aggregation was most strongly correlated with palmitoleic (16:1) and oleic (18:1) LPA and LPC concentrations at all time points. The ingestion of these agents may reduce cardiovascular disease risk in diabetic adults, with a disrupted lipid milieu, via lysolipid mediated mechanisms.

Effects of low-dose aspirin and fish oil on platelet function and NF-kappaB in adults with diabetes mellitus.

INTRODUCTION: Many diabetics are insensitive to aspirin's platelet anti-aggregation effects. The possible modulating effects of co-administration of aspirin and fish oil in subjects with diabetes are poorly characterized. PARTICIPANTS AND METHODS: Thirty adults with type 2 diabetes mellitus were treated with aspirin 81 mg/d for 7 days, then with fish oil 4 g/day for 28 days, then the combination of fish oil and aspirin for another 7 days. RESULTS: Aspirin alone and in combination with fish oil reduced platelet aggregation in most participants. Five of 7 participants classified as aspirin insensitive 1 week after daily aspirin ingestion were sensitive after the combination. Although some platelet aggregation measures correlated positively after aspirin and fish oil ingestion alone and (in combination) in all individuals, correlation was only observed in those who were aspirin insensitive after ingestion of the combination. CONCLUSIONS: Co-administration of aspirin and fish oil may reduce platelet aggregation more than aspirin alone in adults with diabetes mellitus.

The combination of EPA+DHA and low-dose aspirin ingestion reduces platelet function acutely whereas each alone may not in healthy humans.

INTRODUCTION: Aspirin's effectiveness in reducing cardiovascular disease events is inadequate in some individuals, a phenomenon termed aspirin "resistance". The hypothesis that combining low dose aspirin with eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) reduces platelet function in the acute setting has not been investigated. PATIENTS AND METHODS: We conducted a clinical trial of EPA+DHA and aspirin ingestion in healthy adults. Fasting blood samples were drawn at baseline and 4 h after supplementation with EPA/DHA (3.4 g/d), aspirin (81 mg), and both. Platelet function was measured using the Platelet Function Analyzer-100 (PFA-100). Plasma lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), autotaxin, angiogenesis activators, and cytokines were measured. RESULTS: Platelet function decreased with the combination of aspirin+EPA/DHA (p=0.03) but not with either alone (p>0.05). EPA-LPC increased (p=0.002). DISCUSSION AND CONCLUSIONS: Our results demonstrate that a potentially beneficial effect on platelet function occurred within 4h after ingestion of low-dose aspirin and EPA+DHA in healthy adults.

Fatty acids in cardiovascular health and disease: a comprehensive update.

Research dating back to the 1950s reported an association between the consumption of saturated fatty acids (SFAs) and risk of coronary heart disease. Recent epidemiological evidence, however, challenges these findings. It is well accepted that the consumption of SFAs increases low-density lipoprotein cholesterol (LDL-C), whereas carbohydrates, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) do not. High-density lipoprotein (HDL)-C increases with SFA intake. Among individuals who are insulin resistant, a low-fat, high-carbohydrate diet typically has an adverse effect on lipid profiles (in addition to decreasing HDL-C, it also increases triglyceride and LDL particle concentrations). Consequently, a moderate fat diet in which unsaturated fatty acids replace SFAs and carbohydrates are not augmented is advised to lower LDL-C; compared with a low-fat diet, a moderate-fat diet will lower triglycerides and increase HDL-C. Now, there is some new evidence that is questioning the health benefits of even MUFAs and PUFAs. In addition, in a few recent studies investigators have also failed to demonstrate expected cardiovascular benefits of marine-derived omega-3 fatty acids. To clarify the clinical pros and cons of dietary fats, the National Lipid Association held a fatty acid symposium at the 2011 National Lipid Association Scientific Sessions. During these sessions, the science regarding the effects of different fatty acid classes on coronary heart disease risk was reviewed.

Altered cholesterol and fatty acid metabolism in Huntington disease.

Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.

EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls.

BACKGROUND: Increased blood levels of the omega-3 fatty acids (FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been inversely associated with risk for sudden cardiac death, but their relationship with acute coronary syndromes (ACS) is unclear. OBJECTIVE: We hypothesized that the EPA+DHA content of blood cell membranes, as a percent of total FAs, is reduced in ACS patients relative to matched controls. METHODS: We measured the content of EPA+DHA in 768 ACS patients and 768 age-, sex- and race-matched controls. The association with ACS case status of blood cell EPA+DHA [both by a 1 unit change and by category (low, <4%; intermediate 4.1-7.9%; and high, > or =8%)] was assessed using multivariate conditional logistic regression models adjusting for matching variables and smoking status, alcohol use, diabetes, body mass index, serum lipids, education, family history of coronary artery disease, personal histories of myocardial infarction and hypertension, and statin, aspirin, and other antiplatelet drug use. RESULTS: The combined groups had a mean age of 61+/-12 years, 66% were male, and 92% were Caucasian. The EPA+DHA content was 20% lower in cases than controls (3.4+/-1.6 vs. 4.25+/-2.0%, p<0.001). The multivariable-adjusted odds for case status was 0.77 (95% CI 0.70 to 0.85, p<0.001) for a 1 unit increase in EPA+DHA content. Compared with the lowest EPA+DHA group, the odds ratio for an ACS event was 0.58 (95% CI 0.42-0.80), in the intermediate EPA+DHA group and was 0.31 (95% CI 0.14-0.67; p for trend <0.0001) in the highest EPA+DHA group. CONCLUSIONS: Odds for ACS case status increased incrementally as the EPA+DHA content decreased suggesting that low EPA+DHA may be associated with increased risk for ACS.

Determinants of Blood Cell Omega-3 Fatty Acid Content.

BACKGROUND: Although red blood cell eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) content (the Omega-3 Index) predicts cardiovascular death, the factors determining the Index are unknown. METHODS: In 704 outpatients, we undertook an investigation of the clinical determinants of the Index. RESULTS: Factors associated with the Index in decreasing order were: EPA+DHA supplement use, fish consumption frequency, triglyceride level, age, high cholesterol history, and smoking. These factors explained 59% of Index variability, with capsules/fish intake together accounting for 47%. The Index increased by 13% (p< 0.0001) for each serving level increase in fish intake and EPA+DHA supplementation correlated with a 58% increase (p< 0.0001) regardless of background fish intake (p=0.25; test for interaction). A 100 mg/dL decrease in serum triglycerides was associated with a 15% higher (p<0.0001) Index. CONCLUSIONS: The intake of EPA+DHA-rich foods and supplements principally determined the Omega-3 Index, but explained only about half of the variability.