Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study
Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study
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DOI：
10.1016/j.atherosclerosis.2010.08.053
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发表时间：
2010-11-01
期刊：
影响因子：
5.3
通讯作者：
Dolle, Martijn E. T.
中科院分区：
文献类型：
--
作者：
Lu, Yingchang;Feskens, Edith J. M.;Dolle, Martijn E. T.
背景：血浆总胆固醇 (TC) 水平高度由遗传决定。尽管已经报道了单独脂蛋白胆固醇水平的遗传测定的充分证据，但迄今为止，在相对较大的基于广泛基因的关联研究中，尚未报道使用TC水平直接作为表型。方法和结果：我们根据与胆固醇代谢潜在相关的途径，对3575名受试者的243个基因的361个单核苷酸多态性（SNP）进行了基因分型，这些受试者在11年中进行了三次检查。经过多次测试调整后，23 个 SNP 与 TC 水平相关。我们使用了其中的12个（APOE中的rs7412和rs429358，CELSR2中的rs646776，APOB中的rs1367117，ABCG5中的rs6756629，APOA5中的rs662799，LDLR中的rs688，DOCK7中的rs10889353，DOCK7中的rs2304130 NCAN、HMGCR 中的 rs3846662、ABCA1 中的 rs2275543、SMARCA4 中的 rs7275）在之前的候选关联或全基因组关联研究中得到证实，用于定义基因风险评分 (GRS)。胆固醇升高等位基因为 11 或更少的患者的平均 TC 水平从 5.23 +/- 0.82 mmol/L 增至 18 或更多的患者的 6.03 +/- 1.11 mmol/L（P 为趋势）
Background: Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date.Methods and results: We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 +/- 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 +/- 1.11 mmol/L for those with 18 or more (P for trend