Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome.
Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome.
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DOI：
10.1093/hmg/ddab002
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发表时间：
2021-04-30
影响因子：
3.5
通讯作者：
Keavney BD
中科院分区：
文献类型：
--
作者：
McGurk KA;Williams SG;Guo H;Watkins H;Farrall M;Cordell HJ;Nicolaou A;Keavney BD
N-酰基乙醇胺（NAE）和神经酰胺（CER）类信号脂质已成为心血管疾病（CVD）的潜在生物标志物。我们试图确定血浆NAE（包括内源性大麻素anandamide）和CER的遗传性，以确定影响可遗传脂质循环浓度的常见DNA变体，并使用2样本孟德尔随机化（2 SMR）评估这些脂质与CVD的因果关系。采用靶向超高效液相色谱-串联质谱法，对来自196个英国白人家庭的999名成员的血浆样本中的9种NAE和16种CER进行了分析。所有脂质都是显著可遗传的（h2 = 36-62%）。编码脂肪酸酰胺水解酶（FAAH）的基因中的一个错义变体（rs 324420）可降解NAE，在全基因组关联研究（GWAS）显着性（P < 5 × 10 - 8）中与四种NAE（DHEA、PEA、莱亚和VEA）相关。对于CER，SPTLC 3基因中的rs680379编码CER生物合成中限速酶的亚基，与一系列物种相关（例如CER[N（24）S（19）]; P = 4.82 × 10−27）。我们观察到CD 83、SGPP 1和DEGS 1基因座的SNP与血浆CER性状之间存在三种新的关联（P < 5 × 10−8）。2使用我们基于家族的GWAS的遗传工具，在CARDIOGRAMplusC 4D队列（60 801例; 123 504例对照）和DIAGRAM队列（26 488例; 83 964例对照）中进行的SMR未显示CER水平的遗传决定差异与CVD或糖尿病之间的关联。两个新的GWAS基因座SGPP 1和DEGS 1通过UK Biobank、INTERVAL和UKBiLEVE队列（n = 110 000-350 000）中的2SMR表明CER与一系列血液学表型之间存在因果关系。
Signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes have emerged as potential biomarkers of cardiovascular disease (CVD). We sought to establish the heritability of plasma NAEs (including the endocannabinoid anandamide) and CERs, to identify common DNA variants influencing the circulating concentrations of the heritable lipids, and assess causality of these lipids in CVD using 2-sample Mendelian randomization (2SMR). Nine NAEs and 16 CERs were analyzed in plasma samples from 999 members of 196 British Caucasian families, using targeted ultra-performance liquid chromatography with tandem mass spectrometry. All 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 genome-wide association study (GWAS) significance (P < 5 × 10−8) with four NAEs (DHEA, PEA, LEA and VEA). For CERs, rs680379 in the SPTLC3 gene, which encodes a subunit of the rate-limiting enzyme in CER biosynthesis, associated with a range of species (e.g. CER[N(24)S(19)]; P = 4.82 × 10−27). We observed three novel associations between SNPs at the CD83, SGPP1 and DEGS1 loci, and plasma CER traits (P < 5 × 10−8). 2SMR in the CARDIoGRAMplusC4D cohorts (60 801 cases; 123 504 controls) and in the DIAGRAM cohort (26 488 cases; 83 964 controls), using the genetic instruments from our family-based GWAS, did not reveal association between genetically determined differences in CER levels and CVD or diabetes. Two of the novel GWAS loci, SGPP1 and DEGS1, suggested a casual association between CERs and a range of haematological phenotypes, through 2SMR in the UK Biobank, INTERVAL and UKBiLEVE cohorts (n = 110 000–350 000).
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