Plasma Phospholipid Fatty Acid Research Articles

Using Genetic Variants to Evaluate the Causal Effect of Plasma Phospholipid Fatty Acids on Breast Cancer and Prostate Cancer: A Mendelian Randomization Study.

BackgroundObservational studies indicate that phospholipid fatty acids (FAs) have an impact on the etiology in cancers, but the results are conflicting. We aimed to investigate the causal association of phospholipid FAs with breast cancer and prostate cancer.MethodsFourteen single nucleotide polymorphisms (SNPs) were selected as instrumental variables to predict the level of 10 phospholipid FAs from Genome-wide association studies (GWAS). We obtained the summary statistics for the latest and largest GWAS datasets for breast cancer (113,789 controls and 133,384 cases) and prostate cancer (61,106 controls and 79,148 cases) from the Breast Cancer Association Consortium (BCAC) and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Two-sample Mendelian randomization analysis was applied.ResultsThe results demonstrate that the 10 individual plasma phospholipid FAs are not significantly associated with breast cancer risk and prostate cancer risk.ConclusionThe evidence is insufficient to support the causal association of the 10 individual plasma phospholipid FAs with breast cancer and prostate cancer.

159-OR: Changes of Plasma Phospholipid Fatty Acids in Pregnancy in Relation to the Diagnosis and Treatment of Gestational Diabetes

Background: Previous studies have shown that phospholipids fatty acid (FA) levels in early and mid-pregnancy were associated with incident gestational diabetes mellitus (GDM). However, the subsequent changes of such FAs profile following GDM diagnosis/treatment are understudied. Methods: Within the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2,802 pregnant women, we ascertained 85 GDM cases according to Carpenter and Coustan criteria, and 85 non-GDM controls matched on maternal age, race/ethnicity, and gestational week at voluntary blood collection. We quantified participants’ plasma FAs concentrations via gas chromatography prior to GDM diagnosis (23-31 weeks) and after GDM treatment initiation (33-39 weeks), respectively. We estimated the GDM-specific FAs changes before and after GDM diagnosis, in reference to the controls using multiple linear mixed models adjusting for major confounders including pre-pregnancy BMI. Results: Eleven FAs exhibited distinctive pre- and post-GDM diagnosis changes among GDM cases. Compared with controls, GDM cases tended to have greater reduction in GDM risk-related FAs such as 14:0 (β -0.22; 95% CI: -0.30, -0.14), 16:0 (-0.02; -0.04, -0.01) and palmitoleic acid (16:1n7) (-0.02; -0.04, -0.01), while greater increment in GDM protective FAs such as heptadecanoic acid (17:0) (0.17; 0.11, 0.22), vaccenic acid (18:1n7) (0.06; 0.03, 0.10) and DHA (22:6n3) (0.08; 0.02, 0.15). Conclusion: Our data identified distinctive FAs changes between pre- and post GDM diagnosis among GDM subjects. These novel findings, along with prior evidence between antenatal FAs and incident GDM, shed lights on further understanding the FAs metabolism in the GDM etiological relevance. Disclosure L. Li: None. Y. Zhu: None. J. Wu: None. D. K. Tobias: None. S. Hinkle: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. M. Y. Tsai: None. C. Zhang: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development(HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C, HHSN275201000001Z)

Prepubertal Dietary and Plasma Phospholipid Fatty Acids Related to Puberty Timing: Longitudinal Cohort and Mendelian Randomization Analyses.

Dietary intakes of polyunsaturated, monounsaturated and saturated fatty acids (FAs) have been inconsistently associated with puberty timing. We examined longitudinal associations of prepubertal dietary and plasma phospholipid FAs with several puberty timing traits in boys and girls. In the Avon Longitudinal Study of Parents and Children, prepubertal fat intakes at 3–7.5 years and plasma phospholipid FAs at 7.5 years were measured. Timings of Tanner stage 2 genital or breast development and voice breaking or menarche from repeated reports at 8–17 years, and age at peak height velocity (PHV) from repeated height measurements at 5–20 years were estimated. In linear regression models with adjustment for maternal and infant characteristics, dietary substitution of polyunsaturated FAs for saturated FAs, and higher concentrations of dihomo-γ-linolenic acid (20:3n6) and palmitoleic acid (16:1n7) were associated with earlier timing of puberty traits in girls (n = 3872) but not boys (n = 3654). In Mendelian Randomization models, higher genetically predicted circulating dihomo-γ-linolenic acid was associated with earlier menarche in girls. Based on repeated dietary intake data, objectively measured FAs and genetic causal inference, these findings suggest that dietary and endogenous metabolic pathways that increase plasma dihomo-γ-linolenic acid, an intermediate metabolite of n-6 polyunsaturated FAs, may promote earlier puberty timing in girls.

Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up=15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 =0.80; 95%CI:0.69-0.92), myristic acid (HRQ5vsQ1 =0.83, 95%CI:0.74-0.93) and palmitic acid (HRQ5vsQ1 =0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 =0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 =1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR1-SD =0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR1-SD =1.04, 95%CI:0.95-1.15, Pheterogeneity =0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1-SD =1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.

Altered Indices of Fatty Acid Elongases ELOVL6, ELOVL5, and ELOVL2 Activities in Patients with Impaired Fasting Glycemia

Background: Dysregulation of fatty acids (FA) seems to participate in the pathogenesis of disorders such as metabolic syndrome (MetS), cardiovascular diseases, or some cancers. Activities of enzymes FA desaturases and elongases [elongation of very long-chain fatty acid (ELOVL)] significantly influence FA profile in different body compartments. Although the impact of activities of desaturases on cardiometabolic diseases was broadly studied, relatively little attention was devoted to the role of elongases. Methods: Case-control study was carried out in 36 patients (18 men/18 women) with impaired fasting glycemia (IFG) without MetS and 36 age and gender-matched healthy controls. FA profiles in plasma phospholipids (PL) were assessed using gas chromatograph-flame ionization detector and indices of desaturase and elongase activities were calculated. Results: In the IFG group, we observed decreased estimated activities of ELOVL2 and ELOVL5, whereas higher estimated activities of elongase ELOVL6 were noted. IFG group was also characterized by altered composition of plasma PL FA, above all by lower percentage of cis-vaccenic acid (cVA; 18:1n-7) and of total polyunsaturated FA n-6, especially linoleic acid, and by higher proportion of stearic acid and gamma-linolenic acid. Concurrently, elevated estimated activities of desaturases delta-9-desaturase (D9D), D6D were found. Conclusions: Lower estimated activities of ELOVL2 and ELOVL5 with lowered proportion of PL cVA could be associated with disturbances of glucose homeostasis development and their corresponding indices could serve as biomarkers of such risk.

Eicosapentaenoic Acid Increases Plasma ω‐3 Fatty Acids in Hyperlipidemic Children: A Cardioprotective Nutrient?

Background Hyperlipidemic children are at high risk for early coronary heart disease (CHD). Low tissue levels of ω-3 fatty acids are inversely associated with CHD. Previous studies show that high levels of plasma ω-3 fatty acids, eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) from a seafood diet, are associated with an increased likelihood of healthy aging. The Mediterranean diet rich in EPA and docosahexaenoic (DHA) acids is also associated with decreased risk of CHD. These long chain fatty acids positively influence vascular function and reduce CHD by altering membrane fluidity, receptor activity, gene expression and eicosanoid synthesis. The purpose of this study was to determine the effect of the Mediterranean diet alone or combined with EPA on the plasma fatty acid profile of hyperlipidemic children. Methods A randomized, double-blind, placebo-controlled trial was conducted in 6 children (9-16 yrs) with hyperlipidemia. The Mediterranean diet was consumed for 6 wks, followed by the diet combined with EPA supplements (1.2 gms/day) for 6 wks. A Mediterranean diet score was obtained at baseline and after the diet. Plasma phospholipid fatty acid composition was also determined. Plasma was extracted in chloroform:methanol and thin-layer chromatography was used to separate phospholipid fractions. Fatty acid methyl esters were quantified using gas chromatography and identified with standards and expressed as % of total fatty acids. Results Mean Mediterranean diet scores were significantly increased (Baseline: 5.5 ± 0.5 vs Diet: 8.0 ± 1.3; P <.002) verifying dietary compliance. A significant increase in plasma EPA and DPA and a significant decrease in total ω-6 fatty acids and the Arachidonic Acid/EPA Ratio were observed in hyperlipidemic children following EPA supplementation. Conclusion This is the first study to show that EPA supplementation favorably alters the plasma fatty acid composition in hyperlipidemic children by increasing circulating ω-3 fatty acids, EPA, DPA, but not DHA. Studies suggest that increased plasma EPA and DPA are associated with decreased risk of CHD events and greater likelihood of healthy aging. Therefore, these changes may favorably alter pathophysiological vascular processes in hyperlipidemic children and prevent the development of early CHD.

A Prospective Analysis of Plasma Phospholipid Fatty Acids and Breast Cancer Risk in 2 Provinces in Canada.

ABSTRACTBackgroundStudies suggest that fatty acid status influences breast cancer etiology, yet the roles of individual fatty acids in breast cancer risk are unclear, specifically when central adiposity and menopausal status are considered.ObjectivesThis study examined the associations of fatty acid status with breast cancer risk including location, menopausal status, and waist-to-hip ratio as key variables.MethodsPrediagnostic plasma phospholipid fatty acids were measured in women with breast cancer (n = 393) and age-matched controls (n = 786) from a nested case-control prospective study within Alberta's Tomorrow Project (ATP) and British Columbia Generations Project (BCGP) cohorts. Binary logistic regression models were used to evaluate associations of fatty acids and breast cancer risk with subgroup analysis for menopausal status and waist-to-hip ratio.ResultsWomen from BCGP had a higher n–3 (ɷ-3) fatty acid status compared with the ATP (6.4% ± 0.08% vs. 5.3% ± 0.06%; P < 0.001), so subsequent analysis was blocked by cohort. Overall, fatty acids had inconsistent associations with risk. In the ATP among premenopausal women, total long-chain n–3 fatty acids (ORQ4vsQ1 = 1.78; 95% CI: 0.58, 5.43; P-trend = 0.007, P-interaction = 0.07) were positively associated with breast cancer risk, whereas in BCGP, DHA (ORQ4vsQ1 = 0.66; 95% CI: 0.28, 1.53; P-trend = 0.03, P-interaction = 0.05) and total long-chain n–3 fatty acids (ORQ4vsQ1 = 0.66; 95% CI: 0.28, 1.54; P-trend = 0.03) were associated with decreased cancer risk when the waist-to-hip ratio was <0.85.ConclusionsOur findings suggest that regional variations in fatty acid status influence breast cancer risk, resulting in positive associations of total long-chain n–3 fatty acids in premenopausal ATP women and negative associations of these fatty acids in BCGP women with a waist-to-hip ratio below guidelines. This study highlights the complexity and difficulty in using fatty acid status to predict breast cancer risk in diverse populations without the consideration of other risk factors.

Diet intervention improves cardiovascular profile in patients with rheumatoid arthritis: results from the randomized controlled cross-over trial ADIRA

BackgroundThe chronic inflammation in patients with rheumatoid arthritis (RA) increases the risk for cardiovascular diseases (CVD). The contribution of diet as a risk factor for CVD among these patients is however not fully understood. The aim of this study is to investigate if a proposed anti-inflammatory diet improves cardiovascular profile in weight stable patients with RA.MethodsPatients (n = 50) with RA were included in a cross-over trial. They were randomized to either a diet rich in whole grain, fatty fish, nuts, vegetables and fruit and supplemented with probiotics, or a control diet resembling average nutritional intake in Sweden, for ten weeks. After a 4-month washout they switched diet. Participants received food bags and dietary guidelines. Primary outcome was triglyceride (TG) concentration. Secondary outcomes were total-, high density lipoprotein- (HDL) and low density lipoprotein- (LDL) cholesterol, Apolipoprotein-B100 and -A1, lipoprotein composition, plasma phospholipid fatty acids and blood pressure.ResultsForty-seven patients completed at least one period and they remained weight stable. There was a significant between-dietary treatment effect in TG and HDL-cholesterol concentration in favor of intervention (p = 0.007 and p = 0.049, respectively). Likewise, Apolipoprotein-B100/A1 ratio shifted toward a less atherogenic profile in favor of the intervention (p = 0.007). Plasma fatty acids increased in polyunsaturated- and decreased in monounsaturated- and saturated fatty acids between diet periods in favor of the intervention period.ConclusionBlood lipid profile improved indicating cardioprotective effects from an anti-inflammatory dietary intervention in patients with RA.Trial registrationThis trial is registered at ClinicalTrials.gov as NCT02941055.

Is There a FADS2-Modulated Link between Long-Chain Polyunsaturated Fatty Acids in Plasma Phospholipids and Polyphenol Intake in Adult Subjects Who Are Overweight?

Dietary polyphenols promote cardiometabolic health and are linked with long-chain polyunsaturated fatty acids in plasma phospholipids (LC-PUFA). The FADS2 polymorphisms are associated with LC-PUFA metabolism and overweight/obesity. This 4-week study examined the link between polyphenol intake, FADS2 variants (rs174593, rs174616, rs174576) and obesity in 62 overweight adults (BMI ≥ 25), allocated to consume 100 mL daily of either: Aronia juice, a rich source of polyphenols, with 1177.11 mg polyphenols (expressed as gallic acid equivalents)/100 mL (AJ, n = 22), Aronia juice with 294.28 mg polyphenols/100 mL (MJ, n = 20), or nutritionally matched polyphenol-lacking placebo as a control (PLB, n = 20). We analyzed LC-PUFA (% of total pool) by gas chromatography and FADS2 variants by real-time PCR. Four-week changes in LC-PUFA, BMI, and body weight were included in statistical models, controlling for gender and PUFA intake. Only upon AJ and MJ, the presence of FADS2 variant alleles affected changes in linoleic, arachidonic, and eicosapentaenoic acid (EPA). Upon MJ treatment, changes in EPA were inversely linked with changes in BMI (β= −0.73, p = 0.029) and weight gain (β= −2.17, p = 0.024). Only in subjects drinking AJ, the link between changes in EPA and anthropometric indices was modified by the rs174576 variant allele. Our results indicate the interaction between FADS2, fatty acid metabolism, and polyphenol intake in overweight subjects.

A Validated Method for Quantification of Fatty Acids Incorporated in Human Plasma Phospholipids by Gas Chromatography-Triple Quadrupole Mass Spectrometry.

Fatty acids (FA) are important mediators of health maintenance and disease risk. Optimal quantification assays of FA in high and low abundance as well the identification of 13C-labeled tracers to monitor FA metabolism are of major interest. The article on hand reports about the development and validation of a gas chromatography (GC)–triple quadrupole mass selective detection (GC-TQMS) method for absolute quantification of FA in human plasma phospholipids (hpPL). The quantification of the calibration solution by GC–flame ionization detection (GC-FID), with the introduction of a correction factor, allows the direct comparison of individual FA concentrations in hpPL by GC-TQMS. Specificity, sensitivity, and reproducibility are achieved by optimized chromatographic separation and employment of GC-TQMS. The inter-method comparison between GC-FID and GC-TQMS concentrations revealed good comparability for 27 FA. A full validation has been performed with linearity over 4 magnitudes, a limit of detection of 0.18–38.3 fmol on column, a recovery of 83.6–109.6%, and intraday and interday precision data meeting the criteria of EMA and FDA guidelines. The method includes the absolute quantification of 58 positional and geometrical (cis/trans) isomeric FA in hpPL in the concentration range of 1–3000 nmol/mL, covering also low abundant positional cis/trans isomers. Results obtained from both methods are highly comparable, and selectivity and sensitivity are improved by using GC-TQMS. Additionally, we show here that calculation of 13C-labeled C16:0 tracer/tracee ratios in hpPL in human isotope enrichment studies is possible.

Plasma omega-3 and saturated fatty acids are differentially related to pericardial adipose tissue volume across race/ethnicity: the Multi-ethnic Study of Atherosclerosis.

BACKGROUND:Pericardial adipose tissue (PAT) is a cardiometabolic risk factor influenced by race/ethnicity, inflammation, and metabolic dysfunction. Omega-3 fatty acids (FAs) and saturated FAs (SFAs) are known to affect these latter phenomena and may influence PAT accumulation. We aimed to determine whether plasma levels of these FAs are related to PAT volume and its rate of change over a median 3-year follow-up.METHODS:Cardiac computed tomography assessed PAT in 6,785 Multi-Ethnic Study of Atherosclerosis participants. Gas chromatography flame-ionization estimated plasma phospholipid fatty acids. Regression analyses estimated associations of FAs with PAT volume and its rate of change with adjustments for other risk factors. Race-interactions were tested.RESULTS:In cross-section, top tertiles of omega-3 FAs and odd-chained SFAs were associated with 2.8 and 4.93 cm3 lower PAT volumes, respectively; race/ethnicity was a significant modifying variable (p<0.002). Even-chained SFAs were associated with 3.5 cm3 greater PAT volume. With stratification by race/ethnicity, Chinese Americans in the top tertile of omega-3 FAs showed 10.5 cm3 greater PAT volume than those in the referent tertile. Black individuals in the top tertile of odd-chained SFAs showed 5.0 cm3 lower PAT compared to referents. Black and Chinese Americans in top tertiles of even-chained SFAs showed respective 3.7 and 5.9 cm3 greater PAT volumes compared to referents. Two associations were observed in prospective analyses among Caucasians; race interactions were non-significant.CONCLUSIONS:Cross-sectional and prospective findings provide inconclusive evidence as to whether plasma FAs are related to PAT in healthy individuals. Cohort studies with longer follow-up periods are warranted.

Plasma phospholipid fatty acid profiles confirm compliance to the dietary exchange of saturated with unsaturated fat in healthy men using full-fat or lower-fat dairy foods: results from the Reading, Imperial, Surrey, Saturated fat, Cholesterol Intervention (RISSCI) study

Plasma phospholipid fatty acid profiles confirm compliance to the dietary exchange of saturated with unsaturated fat in healthy men using full-fat or lower-fat dairy foods: results from the Reading, Imperial, Surrey, Saturated fat, Cholesterol Intervention (RISSCI) study

Plasma phospholipid fatty acids, cognitive function, and risk of dementia among older adults

AbstractBackgroundPlasma phospholipids are biomarkers of dietary fat intake and metabolism which have been linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to adjudicated dementia risk and cognitive decline.MethodWe measured plasma phospholipids in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 911 randomly selected participants and 498 participants who developed dementia during a mean [SD] of 5.0 [1.8] years of follow‐up. We measured individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by gas chromatography with flame ionization detection. These were evaluated in association with the Modified Mini‐Mental State Examination (3MSE) scores at baseline and neurologist‐adjudicated risks of all‐cause dementia and Alzheimer’s disease (AD), adjusting for sociodemographic and clinical characteristics.ResultWhen compared with saturated fatty acids (SFA), we found no associations of total mono‐unsaturated (MUFA), polyunsaturated (PUFA), or trans‐fatty acids (TFA) with risk of dementia or AD. However, higher docosahexaenoic acid was associated with a lower risk of dementia (hazard ratio 0.80 per 1% of docosahexaenoic acid instead of SFA; 95% confidence interval: 0.71‐0.91). Similarly, higher PUFA was associated with 0.04 point higher 3MSE score at baseline (per 1% PUFA instead of SFA; 95% confidence interval: 0.01, 0.08) signifying better cognitive function.ConclusionsAlthough we did not find strong associations of mono‐unsaturated or TFA with risk of dementia or AD when compared with SFA, replacement with PUFA was associated with better baseline cognitive function, and replacement with the marine n‐3 fatty acid docosahexaenoic acid was associated with lower risk of dementia. This prospective study highlights the potential of dietary improvement to prevent dementia.

Influence of fish oil on plasma phospholipid fatty acid composition in lung cancer patients

Rationale: Marine n-3 fatty acids have well-known anti-inflammatory effects, and may be used as a nutritional support for cancer patients. In this study, we investigated the effect of fish oil supplementation on changes in the plasma phospholipid fatty acid (FA) profile of patients with non-small lung cancer receiving primary anti-neoplastic treatment.

Colostrum supplementation with n-3 fatty acids alters plasma polyunsaturated fatty acids and inflammatory mediators in newborn calves

Calves may experience increased oxidative stress at birth through activation of metabolic and respiratory processes. Reducing oxidative stress may enhance calf viability in early life. Our objective was to determine the dose response to fish and flaxseed oil when supplemented in colostrum on concentrations of plasma fatty acid (FA), FA metabolites, and index of oxidative stress during the critical first week of life in calves to understand how supplementing n-3 FA may decrease oxidative stress. We hypothesized that n-3 FA supplemented in colostrum in a linear dose-dependent fashion would associate with increased plasma n-3 FA concentrations and decreased oxidative stress. Twenty-four male and female Holstein calves were randomly assigned to receive 0, 30, 60, or 120 mL of a 1:1 fish to flaxseed oil supplement in colostrum. All calves received 2.8 L of previously frozen colostrum (≥22% Brix) with their respective treatment within 6 h after birth. Blood was sampled before first feeding after birth and on d 1, 2, 4, 7, and 14 d of age to assess oxidant status and plasma free PUFA, phospholipid FA, and oxylipid concentrations. Health indicators were observed daily. Indicators of general health and growth were unaffected by treatment. Supplemented calves exhibited greater concentrations of n-3 FA in plasma as free and phospholipid FA and some n-3 and n-6 FA-derived oxylipids in the first week of life in a linear fashion with increasing supplemental dose. Fish and flaxseed oil treatments did not alter oxidant status but overall decreased isoprostane concentrations in plasma, indicating oxidative stress was decreased. Together, these responses indicate that the fish and flaxseed oil supplement was antiinflammatory. In conclusion, supplementing colostrum with 30, 60, and 120 mL of a 1:1 mixture of fish and flaxseed oil linearly increased plasma concentrations of n-3 FA and metabolites and decreased biomarkers of oxidative stress, but did not alter oxidant status or affect health or growth. Our findings suggest neonatal calves may benefit from n-3 FA supplementation in colostrum to encourage a greater antiinflammatory state.

FADS2 polymorphisms are associated with plasma arachidonic acid and estimated desaturase-5 activity in a cross-sectional study

Polymorphisms in FADS genes are associated with plasma long-chain polyunsaturated fatty acids (LC-PUFA) and modulate omega-6/omega-3 balance. We hypothesized that the FADS2 gene variants will be associated with lower product-to-precursor ratio in the fatty acid metabolic pathways. Thus, we explored FADS2 rs174593, rs174616, and rs174576 effects on plasma phospholipid fatty acid profile, markers of desaturase activities, and risk factors in a sample of apparently healthy Serbian adults. Food and nutrient intake data were compiled through 24 h recalls. Plasma phospholipid fatty acid content was assessed by gas-chromatography. Estimated desaturase activities were calculated as conversion rates towards LC-PUFA in omega-6 pathway. During the selection of FADS2 polymorphisms, we accounted for their positional and functional aspect. Genotyping was performed by Real-Time PCR. Multivariable-adjusted general linear and hierarchical regression models were applied. Study subjects (mean age = 40 ± 7 years, 70% who were overweight) had a median dietary omega-6/omega-3 ratio of 16.29. Alternative allele frequencies were 33%, 36%, and 51% for rs174593, rs174576, and rs174616, respectively. Addition of FADS2 alternative alleles was associated with lower plasma arachidonic acid (AA, C20:4 n-6, P < .001) and estimated desaturase-5 activity (P < .001), irrespective of gender, age, daily polyunsaturated/saturated fatty acid intake, and obesity. The rs174576 association with AA withstood multiple testing and additional adjustments for other variants (multivariable-adjusted β = −1.14 [95% CI: −2.25, −0.43]). None of the variants was associated with dietary intake, serum lipids, or obesity. We observed inverse associations between FADS2 variants and plasma AA but not omega-3 fatty acids in Serbian subjects, with rs174576 exhibiting the strongest relation.

Plasma Phospholipid Fatty Acids and Breast Cancer Risk in Alberta’s Tomorrow Project

Abstract Objectives It is estimated that lifestyle factors, such as dietary intake, contribute up to 21% of all breast cancer (BC) cases. High dietary intakes of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) have been associated with a reduced incidence of BC. Dietary intake of n-3 LCPUFA typically correlate with blood fatty acid concentrations, but the relationship between blood fatty acid concentrations and BC risk has not yet been established. We hypothesized that higher plasma phospholipid (PL) content of n-3 LCPUFAs would be associated with a reduced risk of BC. Methods Plasma samples and relevant covariables were obtained from 614 age-matched women (203 with BC/411 control) from a nested case-control within Alberta's Tomorrow Project. PL fatty acid concentration and relative % composition were determined from baseline plasma samples (collected 9–16 years pre-BC diagnosis). Principal component analysis was employed to determine predictive models for fatty acid clusters. Conditional logistic regression models controlled for covariates were used to assess the relative risk of BC (odds ratio-OR) by fatty acid content. Sub-group analyses by menopausal status and BMI at baseline were also performed. Results When adjusted for BMI and menopausal status, individual fatty acids, including linoleic acid (OR = 1.75, 95% confidence interval (CI) = 1.08,2.84, P &amp;lt; 0.04) and arachidonic acid (OR = 1.60, 95% CI = 1.03,2.49, P &amp;lt; 0.04), were positively associated with BC risk. However, composite analysis of grouped fatty acids were found to be stronger indicators of risk – total PUFA (µg/mL; OR = 2.25, 95% CI = 1.4,3.44, P &amp;lt; 0.001), total n-6 PUFA (OR = 2.11, 95% CI = 1.32,3.36, P &amp;lt; 0.002), and total n-3 PUFA (OR = 1.57, 95% CI = 1.06,2.32, P &amp;lt; 0.02), were independent predictors of BC risk. Conclusions In contrast to epidemiological dietary evidence, this study found an increased risk of BC with higher plasma concentrations of n-3 LCPUFA. However, the absolute n-3 concentration in this population was low, and therefore a second cohort is being assessed to validate these results. Overall, this study suggests that risk of BC cannot be predicted by isolated fatty acid blood concentrations, but that the balance of different fatty acids or the combination of n-3 and n-6 fatty acids may be a better predictor of BC. Funding Sources Funded by Women and Children's Health Research Institute.

Evaluation of Nutritional, Inflammatory, and Fatty Acid Status in Patients with Gastric and Colorectal Cancer Receiving Chemotherapy

Malnutrition is prevalent in gastrointestinal (GI) cancer patients, possibly due to inflammation and altered fatty acids (FA). There is a lack of research describing nutritional decline in these patients during chemotherapy. We described changes in nutritional, inflammatory, and FA status over time and factors relating to change in nutritional status according to tumor presence in 41 GI cancer patients undergoing first-line treatment over four chemotherapy visits, using linear mixed effects models. At baseline, 53% of patients were malnourished. Over time, there was a decrease in the proportion of malnourished vs. well-nourished individuals (β= −0.564, p < 0.01). Median concentrations of plasma linoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, total n-3, total n-6 and total plasma phospholipid FA increased over time. Changes over time in nutritional status based on weight (p < 0.001), fat free mass (FFM) measured by bioelectrical impedance analysis (BIA, p = 0.02), and skinfold anthropometry (FSA, p = 0.04) were significantly dependent on tumor presence. There were positive associations between weight and total n-3 (β = 0.02, p < 0.01), FFM and IL-6 (BIA, β = 0.028, p = 0.02; FSA, β = 0.03, p = 0.02), and FFM and total n-6 (BIA, β = 0.003, p = 0.01). Changes in nutritional status during chemotherapy were negatively impacted by tumor presence, and were associated with increasing concentrations of cytokines and FA.

A rapid method for the separation of the phospholipids from the neutral lipids in plasma

The blood fraction most commonly used for the assessment of fatty acid status is the plasma or serum phospholipids, since these provide a measure of long term dietary intake. However, conventional assays of fatty acid status in human plasma and serum require labour intensive, multi-step approaches, which are impractical for high-throughput analyses. This study reports a system capable of selectively separating plasma phospholipids from other lipid classes in just a few minutes. We demonstrate that compositional analysis of the fatty acids in plasma phospholipids using our plasma spot method resulted in greater than 97% of neutral lipid standards had been eluted from the paper, whereas more than 96% of the PC remained on the paper. These results were almost identical to conventional methods involving liquid/liquid extraction and thin layer chromatography separation. Evaluation of our plasma spot fractionation and assay using plasma from 110 human subjects (75 males, 35 females), provides confirmation of significant correlations between the fatty acid measures and those obtained from conventional measures for all fatty acids (r > 0.97, P<0.0001), including the omega (n)-6 (r = 0.988, P<0.0001) and n-3 long chain polyunsaturated fatty acids (r = 0.997, P<0.0001). These results establish our newly developed plasma spot separation technique as a rapid and reliable method for the assessment of plasma phospholipid fatty acid composition.

Maternal fatty acid concentrations and newborn DNA methylation

Preconception nutrition sets the stage for a healthy pregnancy. Maternal fatty acids (FAs) are related to beneficial neonatal outcomes with DNA methylation proposed as a mechanism; however, few studies have investigated this association and none with preconception FAs. We examined the relations of maternal plasma FA concentrations at preconception (n=346) and 8 weeks of gestation (n=374) with newborn DNA methylation. The Effects of Aspirin in Gestation and Reproduction Trial (2006-2012) randomly assigned women with previous pregnancy loss to low dose aspirin or placebo prior to conception. We measured maternal plasma phospholipid FA concentration at preconception (on average 4 mo before pregnancy) and 8 weeks of gestation. Cord blood DNA from singletons was measured using the MethylationEPIC BeadChip. We used robust linear regression to test the associations of FA concentration with methylation β-values of each CpG site, adjusting for estimated cell count using a cord blood reference, sample plate, maternal sociodemographic characteristics, cholesterol, infant sex, and epigenetic-derived ancestry. False discovery rate correction was used for multiple testing. Mean ± SD concentrations of preconception marine (20:5n-3+22:6n-3+22:5n-3) and ω-6 PUFAs, SFAs, MUFAs, and trans FAs were 4.7 ± 1.2, 38.0 ± 2.0, 39.4 ± 1.8, 11.6 ± 1.1, and 1.0 ± 0.4 % of total FA, respectively; concentrations at 8 weeks of gestation were similar. Preconception marine PUFA concentration was associated with higher methylation at GRAMD2 (P=1.1×10-8), LOXL1 (P=5.5×10-8), SIK3 (P=1.6×10-7), HTR1B (P=1.9×10-7), and MCC (P=2.1×10-7) genes. Preconception SFA concentration was associated with higher methylation at KIF25-AS1 and lower methylation at SLC39A14; other associations exhibited sensitivity to outliers. The trans FA concentration was related to lower methylation at 3 sites and higher methylation at 1 site. FAs at 8 weeks of gestation were largely unrelated to DNA methylation. Maternal preconception FAs are related to newborn DNA methylation of specific CpG sites, highlighting the importance of examining nutritional exposures preconceptionally. This trial was registered at clinicaltrials.gov as NCT00467363.