Introduction Lipids have key roles in CVD but heritability studies focus on few species bar lipoproteins. Lipids play key roles in cell signalling, immunity, inflammation, vasodilation and cell death. Although not encoded, their activities are tightly linked to DNA-encoded entities (e.g. enzymes and other proteins) and those with a strong genetic influence (high heritability) may identify novel pathways in CVD. Purpose: Analysing eicosanoid, endocannabinoid and sphingolipid profiles in 250 British Caucasian families with GWAS data will identify particularly heritable lipid biomarkers for the discovery of causative genetic variation of CVD.
Methods An array of 79 eicosanoids and related species, 33 endocannabinoids and congeners, 63 ceramides and related species, from 204 plasma samples (31 families of 1+ individuals with hypertension) were extracted and analysed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Quality control was accessed and estimates of heritability of each lipid species was estimated using QTDT software. The concentration of each lipid species were assessed for normal distribution, outliers, and adjusted for age and sex. The resulting lipid concentrations will be analysed using FaST-LMM software for associations with 557,124 SNPs.
Results 19 species of eicosanoids were identified (mean concentrations 19 pg/ml – 7600 pg/ml); the species at highest abundance in plasma (HODEs) are derivatives of the omega-6 fatty acid linoleic acid. 8 species passed quality control assessments and 3 species were estimated to be significantly heritable (9-OxoODE 24%, 12-HETE 44%, 12(13)-EPOME 78%). 15 congeners of endocannabinoids were identified (mean concentrations 20 pg/ml – 4000 pg/ml); the species at highest abundance in plasma are glycerol derivatives. 9 species passed quality control assessments and all were estimated to be significantly heritable (27%–73%)%). 57 species of ceramides were identified (mean concentrations 0.01 pmol/ml – 190 pmol/ml); the species at highest abundance in plasma are NS ceramides involved in apoptosis. 36 species passed quality control assessments and all species were estimated to be significantly heritable (10%–63%)%).
Conclusions We demonstrate for the first time estimates of heritability for an array of bioactive lipids. Although found at concentrations million times lower than cholesterol, many of the heritability estimates are similar to plasma genetic biomarkers of CVD (ACE h2>45%). The association between heritable biomarkers, cardiovascular phenotypes and risk will be determined. Particularly heritable species and those with highly significant hits at GWAS will be profiled in the extended cohort (1400 samples, 250 families) and replication will take place in the UK biobank, or other. A subset of the most heritable species and those with hits at GWAS resulting from the full lipidomic profile of 3 lipidomic classes will be used to identify causal metabolic pathways, novel diagnostics and drug targets for CVD intervention.
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