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Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39?740 adults from 20 prospective cohort studies.

ABSTRACT: BACKGROUND:The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. METHODS:We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. FINDINGS:Participants were 39?740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m2, who did not have type 2 diabetes at baseline. During a follow-up of 366?073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I2=53·9%, pheterogeneity=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I2=63·0%, pheterogeneity<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all pheterogeneity?0·13). INTERPRETATION:Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful. FUNDING:Funders are shown in the appendix.

SUBMITTER: Wu JHY

PROVIDER: S-EPMC6029721 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.

Wu Jason H Y JHY Marklund Matti M Imamura Fumiaki F Tintle Nathan N Ardisson Korat Andres V AV de Goede Janette J Zhou Xia X Yang Wei-Sin WS de Oliveira Otto Marcia C MC Kröger Janine J Qureshi Waqas W Virtanen Jyrki K JK Bassett Julie K JK Frazier-Wood Alexis C AC Lankinen Maria M Murphy Rachel A RA Rajaobelina Kalina K Del Gobbo Liana C LC Forouhi Nita G NG Luben Robert R Khaw Kay-Tee KT Wareham Nick N Kalsbeek Anya A Veenstra Jenna J Luo Juhua J Hu Frank B FB Lin Hung-Ju HJ Siscovick David S DS Boeing Heiner H Chen Tzu-An TA Steffen Brian B Steffen Lyn M LM Hodge Allison A Eriksdottir Gudny G Smith Albert V AV Gudnason Vilmunder V Harris Tamara B TB Brouwer Ingeborg A IA Berr Claudine C Helmer Catherine C Samieri Cecilia C Laakso Markku M Tsai Michael Y MY Giles Graham G GG Nurmi Tarja T Wagenknecht Lynne L Schulze Matthias B MB Lemaitre Rozenn N RN Chien Kuo-Liong KL Soedamah-Muthu Sabita S SS Geleijnse Johanna M JM Sun Qi Q Harris William S WS Lind Lars L Ärnlöv Johan J Riserus Ulf U Micha Renata R Mozaffarian Dariush D

The lancet. Diabetes & endocrinology 20171012 12

<h4>Background</h4>The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes.<h4>Methods</h4>We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident ty ...[more]

PMID: 29032079

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Project description:BackgroundGlobal dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.MethodsWe performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).ResultsIn 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.ConclusionsIn pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Project description:Backgroundn-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.ObjectivesWe sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.MethodsHarmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.ResultsIn pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.ConclusionsParticipants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

Project description:The relationship between omega-3 polyunsaturated fatty acids (n-3 PUFA) from seafood sources (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or plant sources (alpha-linolenic acid, ALA) and risk of type 2 diabetes mellitus (DM) remains unclear. We systematically searched multiple literature databases through June 2011 to identify prospective studies examining relations of dietary n-3 PUFA, dietary fish and/or seafood, and circulating n-3 PUFA biomarkers with incidence of DM. Data were independently extracted in duplicate by 2 investigators, including multivariate-adjusted relative risk (RR) estimates and corresponding 95 % CI. Generalized least-squares trend estimation was used to assess dose-response relationships, with pooled summary estimates calculated by both fixed-effect and random-effect models. From 288 identified abstracts, 16 studies met inclusion criteria, including 18 separate cohorts comprising 540,184 individuals and 25,670 cases of incident DM. Consumption of fish and/or seafood was not significantly associated with DM (n = 13 studies; RR per 100 g/d = 1·12, 95 % CI = 0·94, 1·34); nor were consumption of EPA+DHA (n = 16 cohorts; RR per 250 mg/d = 1·04, 95 % CI = 0·97, 1·10) nor circulating levels of EPA+DHA biomarkers (n = 5 cohorts; RR per 3 % of total fatty acids = 0·94, 95 % CI = 0·75, 1·17). Both dietary ALA (n = 7 studies; RR per 0·5 g/d = 0·93, 95 % CI = 0·83, 1·04) and circulating ALA biomarker levels (n = 6 studies; RR per 0·1 % of total fatty acid = 0·90, 95 % CI = 0·80, 1·00, P = 0·06) were associated with non-significant trend towards lower risk of DM. Substantial heterogeneity (I²~80 %) was observed among studies of fish/seafood or EPA+DHA and DM; moderate heterogeneity ( < 55 %) was seen for dietary and biomarker ALA and DM. In unadjusted meta-regressions, study location (Asia vs. North America/Europe), mean BMI, and duration of follow-up each modified the association between fish/seafood and EPA+DHA consumption and DM risk (P-interaction ? 0·02 each). We had limited statistical power to determine the independent effect of these sources of heterogeneity due to their high collinearity. The overall pooled findings do not support either major harms or benefits of fish/seafood or EPA+DHA on development of DM, and suggest that ALA may be associated with modestly lower risk. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation.

Project description:ObjectiveTo investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD), and progression to geographic atrophy (GA).DesignObservational analysis of a prospective cohort.ParticipantsA total of 2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not.MethodsEyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements, were collected at baseline using questionnaires. Dietary data were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids and interaction effects between dietary fat intake and genetic variation on risk of GA.Main outcome measuresAssociations between dietary fat intake reported from FFQs, genetic variants, and incident GA.ResultsIncreased intake of DHA was significantly associated with reduced risk of progression to GA in models with behavioral factors (model A) plus genetic variants (model B) (P trend = 0.01 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in model B (P trend = 0.02). Monounsaturated fat was associated with increased risk in model A (P trend = 0.05). DHA intake was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002; P for interaction between gene and fat intake = 0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90).ConclusionsIncreased self-reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Project description:BackgroundEarly menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease.MethodsWe harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40-44 years (early menopause), 45-49 years (relatively early), 50-51 years (reference category), 52-54 years (relatively late), and 55 years or older (late menopause).FindingsOverall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50-51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38-1·73; p<0·0001), early menopause (age 40-44 years; 1·30, 1·22-1·39; p<0·0001), and relatively early menopause (age 45-49 years; 1·12, 1·07-1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62-2·20; p<0·0001) and early menopause (1·40, 1·27-1·54; p<0·0001), but were attenuated at age 60-69 years, with no significant association observed at age 70 years and older.InterpretationCompared with women who had menopause at age 50-51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women.FundingAustralian National Health and Medical Research Council.

Project description:IntroductionConflicting findings in both interventional and observational studies have resulted in a lack of consensus on the benefits of ?3 fatty acids in reducing disease risk. This may be due to individual variability in response. We used a multi-platform lipidomic approach to investigate both the consistent and inconsistent responses of individuals comprehensively to a defined ?3 intervention.MethodsThe lipidomic profile including fatty acids, lipid classes, lipoprotein distribution, and oxylipins was examined multi- and uni-variately in 12 healthy subjects pre vs. post six weeks of ?3 fatty acids (1.9 g/d eicosapentaenoic acid [EPA] and 1.5 g/d docosahexaenoic acid [DHA]).ResultsTotal lipidomic and oxylipin profiles were significantly different pre vs. post treatment across all subjects (p=0.00007 and p=0.00002 respectively). There was a strong correlation between oxylipin profiles and EPA and DHA incorporated into different lipid classes (r(2)=0.93). However, strikingly divergent responses among individuals were also observed. Both ?3 and ?6 fatty acid metabolites displayed a large degree of variation among the subjects. For example, in half of the subjects, two arachidonic acid cyclooxygenase products, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), and a lipoxygenase product, 12-hydroxyeicosatetraenoic acid (12-HETE) significantly decreased post intervention, whereas in the other half they either did not change or increased. The EPA lipoxygenase metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) varied among subjects from an 82% decrease to a 5,000% increase.ConclusionsOur results show that certain defined responses to ?3 fatty acid intervention were consistent across all subjects. However, there was also a high degree of inter-individual variability in certain aspects of lipid metabolism. This lipidomic based phenotyping approach demonstrated that individual responsiveness to ?3 fatty acids is highly variable and measurable, and could be used as a means to assess the effectiveness of ?3 interventions in modifying disease risk and determining metabolic phenotype.

Project description:ObjectiveTo investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk.DesignVitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design.SettingNationwide in the United States.Participants25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment.InterventionsVitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence.Main outcome measuresThe primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others.Results25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease.ConclusionsVitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).Study registrationClinicalTrials.gov NCT01351805 and NCT01169259.

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Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39?740 adults from 20 prospective cohort studies.

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Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.

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