《新英格兰》：9个SNPs协同影响血脂和心血管事件

readok2009

Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events

ABSTRACT

Background
Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease.

Methods
We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malm?Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score.

Results
All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score.

Conclusions
A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors.

http://content.nejm.org/cgi/content/short/358/12/1240

摘要
背景
通常单核苷酸多态性与血中低密度脂蛋白或高密度脂蛋白有关并对血脂水平
有轻微影响。我们对单核苷酸多态性与心血管疾病危险性有关的假说进行了研究。
方法
我们把马尔默饮食和癌研究的心血管组的5414位受试者中分成九个亚组来研究单核苷酸多态性。我们首先证实了单核苷酸多态性和低密度脂蛋白或高密度脂蛋白的联系，随后在大量不被接受等位基因的基础上产生了基因型。我们采用cox比例风险模型来评判与基因型有联系的首次心血管事件。
结果
所有九组受试单位均显示单核苷酸多态性与低密度脂蛋白或高密度脂蛋白的联系。随着基因型的升高，低密度脂蛋白升高了152-171mg/ml，（3.9-4.4mmol/l）,然而高密度脂蛋白却下降了60-51mg/ml(1.6-1.3mmol/l).在随访期间（中位数，10.6年），238位受试者发生了首次心血管事件。在考虑血脂基线水平进行相关变异系数调整后，基因型仍然与心血管偶然事件有关（P<0.001）.在使用了C统计值进行评估，基因型不能提高临床危险度的预测。但是，在包含该基因型与不包含该基因型的两组中其心血管事件的危险性差别还是有显著差异的。
结论
该研究证实与调整低密度脂蛋白或高密度脂蛋白有关的单核苷酸多态性的基因型是偶发心血管事件的独立危险因数。基因型不能提高临床危险度的预测，但对个体受试者来说还是比标准临床因数在临床危险分类上有了一定的提高。