Increased Levels of Circulating Fatty Acids Are Associated with Protective Effects against Future Cardiovascular Events in Nondiabetics

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Nontargeted metabolomics analysis was performed by LC–HRMS in combination with targeted quantification of eicosanoids and endocannabinoids. Plasma from 375 individuals from the IMPROVE pan-European cohort was included in a case-control study design. Following data processing, the three metabolite data sets were concatenated to produce a single data set of 267 identified metabolites. Factor analysis identified six factors that described 26.6% of the variability in the given set of predictors. An association with cardiovascular events was only observed for one factor following adjustment (<i>p</i> = 0.026). From this factor, we identified a free fatty acid signature (<i>n</i> = 10 lipids, including saturated, monounsaturated, and polyunsaturated fatty acids) that was associated with lower risk of future cardiovascular events in nondiabetics only (OR = 0.65, 0.27–0.80 95% CI, <i>p</i> = 0.030), whereas no association was observed among diabetic individuals. These observations support the hypothesis that increased levels of circulating omega-6 and omega-3 fatty acids are associated with protective effects against future cardiovascular events. However, these effects were only observed in the nondiabetic population, further highlighting the need for patient stratification in clinical investigations

String-database network connections between proximal cis-gene and target plasma protein.

<p>All short String paths that connect proximal cis-genes with the target plasma protein are shown. The colour intensity of each gene shows the eQTL association-strength with the index-SNP. The nodes highlighted with bold border show paths that satisfy P<0.05 in network permutation analysis. A) the rs61598054-SNP is harboured in an intron of the <i>LACE1</i> gene, but have no paths to the target gene <i>NGF</i> and a more likely mechanism is therefore <i>FOXO3</i> -> <i>AKT1</i> -> <i>NGF</i>, which involves a rs61598054-trans-eQTL effect on <i>AKT1</i>. In permutation analysis of re-wired networks this is stronger than 95% of random networks. B) Similarly for rs693918, while located between <i>SRD5A2</i> and <i>MEMO1</i>, the path <i>XDH</i> -> <i>TLR4</i> -> <i>IL18</i> is a more likely mechanistic path, supported by eQTL effects on both <i>XDH</i> and <i>TLR4</i>. C) The rs61598054-<i>AKT1</i> trans-eQTL from panel A in 235 IFN-stimulated monocytes and the rs10947260-ATF3 trans-eQTL from panel D in 89 mammary artery samples. D) Example of ambiguous findings regarding the rs10947260 -> -> -> IL6: The SNP has a coding-proxy in <i>BTNL2</i>, literature mining evidence for the <i>AGER</i> gene, but also eQTL-weighted pathway evidence for both <i>ATF6B</i> and <i>NOTCH4</i>.</p

Systematic analysis of potential mechanisms behind trans-pQTL associations.

<p>Systematic analysis of potential mechanisms behind trans-pQTL associations.</p

Overview of pQTL associations.

<p>Overview of pQTL associations.</p

Association between pQTLs and Coronary Artery Disease (CAD) risk.

<p>Each SNP from supplemental <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006706#pgen.1006706.s003" target="_blank">S1 Table</a> was investigated in the CARDIoGRAMplusC4D data, and the P-values for the pQTL and CAD risk were extracted. An additional pooled analysis was performed in cases where one plasma protein had multiple pQTLs,. The table shows all pQTLs for which either a single-SNP or pooled CAD association had a P<0.05. P-values highlighted in italics indicate that the association was also significant after FDR correction for multiple testing.</p