Signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes are emerging as novel cardiovascular disease biomarkers. We sought to establish the heritability of plasma NAEs (including the endocannabinoid anandamide) and CERs, and identify common DNA variants influencing the circulating concentrations of the heritable lipid species. Nine NAE and sixteen CER species were analysed in plasma samples from 999 members of 196 British Caucasian families, using targeted mass spectrometry (UPLC-MS/MS). Heritability was estimated and GWAS analyses were undertaken; all target lipids were significantly heritable (h2 = 36%-62%). A missense variant (rs324420) in the gene encoding the enzyme fatty acid amide hydrolase (FAAH), which degrades NAEs, associated at GWAS significance (P<2.15x10-8) with four NAEs (DHEA, PEA, LEA, VEA). The A allele of this SNP was associated with a 0.23 SD per-allele increase in plasma NAE species. Additionally, we found association between rs680379 in the SPTLC3 gene, which encodes a subunit of the rate limiting enzyme in CER biosynthesis, and a range of CER species (e.g. CER[N(24)S(19)]; P =4.82x10-27). We also observed three novel associations (CD83, SGPP1, FBXO28-DEGS1) influencing plasma CER traits, two of which (SGPP1 and DEGS1) implicate CER species in haematological phenotypes. NAE and CER are substantially heritable bioactive lipids, influenced by SNPs in key metabolic enzymes.

中文翻译：

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N-酰基乙醇胺和神经酰胺血浆脂质组的遗传力和基于家族的GWAS分析

N-酰基乙醇胺（NAE）和神经酰胺（CER）类的信号脂质正在作为新型的心血管疾病生物标志物出现。我们寻求建立血浆NAE（包括内源性大麻素南安达酰胺）和CER的遗传力，并确定影响可遗传脂质物种循环浓度的常见DNA变异体。使用靶向质谱法（UPLC-MS / MS）分析了来自196个英国高加索家庭的999名成员的血浆样品中的9种NAE和16种CER。评估遗传力并进行了GWAS分析；所有目标脂质均具有明显的遗传性（h2 = 36％-62％）。编码脂肪酸酰胺水解酶（FAAH）的基因中的错义变体（rs324420），其降解NAE，与四个NAE（DHEA，PEA，LEA，VEA）具有GWAS重要性（P <2.15x10-8）。该SNP的A等位基因与血浆NAE物种每等位基因增加0.23 SD相关。此外，我们发现SPTLC3基因中的rs680379与编码一系列CER的物种（例如CER [N（24）S（19）]； P = 4.82x10- 27）。我们还观察到影响血浆CER性状的三个新型关联（CD83，SGPP1，FBXO28-DEGS1），其中两个（SGPP1和DEGS1）在血液学表型中暗示了CER种类。NAE和CER是基本可遗传的生物活性脂质，受关键代谢酶中SNP的影响。CER [N（24）S（19）]; P = 4.82×10-27）。我们还观察到三个新的关联（CD83，SGPP1，FBXO28-DEGS1）影响血浆CER的性状，其中两个（SGPP1和DEGS1）将CER物种暗示为血液学表型。NAE和CER是基本可遗传的生物活性脂质，受关键代谢酶中SNP的影响。CER [N（24）S（19）]; P = 4.82×10-27）。我们还观察到影响血浆CER性状的三个新型关联（CD83，SGPP1，FBXO28-DEGS1），其中两个（SGPP1和DEGS1）在血液学表型中暗示了CER种类。NAE和CER基本上是可遗传的生物活性脂质，受关键代谢酶中SNP的影响。