Department of Cardiovascular Science, University of Leicester, Leicester, United Kingdom.
PLoS One. 2011 Jan 21;6(1):e14529. doi: 10.1371/journal.pone.0014529.
HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis.
METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.610(-15)) and SGCD (sarcoglycan delta; rs6877118: p = 8.610(-6)). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.110(-9)), PLTP (phospholipid transfer protein, rs4810479: p = 1.710(-8)) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10(-6)). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170).
We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.
高密度脂蛋白胆固醇（HDL-C）是心血管风险的既定标志物，具有显著的遗传决定因素。然而，高密度脂蛋白颗粒并非同质的，精细的高密度脂蛋白表型分析可能会更好地了解 HDL 代谢的调节。因此，我们通过 NMR 光谱法评估了 HDL 颗粒，并进行了大规模候选基因关联分析。
方法/主要发现：我们测量了 2024 名来自 512 个英国白种人家族的个体的血浆 HDL-C，并通过 NMR 光谱法测定了平均 HDL 颗粒大小和颗粒数。基因型为 >2100 个心脏代谢候选基因/基因座的 49094 个 SNP，这些基因/基因座代表在 HumanCVD BeadChip 版本 2 上。为了考虑多重检验，计算了错误发现率（FDR）。对经典 HDL-C 的分析仅显示 CETP（胆固醇酯转移蛋白；先导 SNP rs3764261：p = 5.610(-15)) 和 SGCD（肌聚糖 delta；rs6877118：p = 8.610(-6)) 存在显著关联（FDR<0.05）。相比之下，HDL 平均颗粒大小的分析产生了 LIPC（肝脂肪酶；rs261332：p = 6.110(-9))、PLTP（磷脂转移蛋白，rs4810479：p = 1.710(-8)) 和 FBLN5（纤连蛋白 5；rs2246416：p = 6.2*10(-6)) 的附加关联。在 PROCARDIS（n = 3078）和/或女性基因组健康研究（n = 23170）中，SGCD 和 Fibulin-5 与 HDL 颗粒大小的关联无法复制。
我们表明，通过 NMR 光谱法进行精细的 HDL 表型分析可以比分析 HDL-C 更好地检测到 HDL 代谢的已知基因。
