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NEJM:确认三个冠心病易感基因

来源:科技日报 2009-12-28 10:48

近日,欧洲科学家确认了3个与冠心病有关的基因,证实了两个单核苷酸多态性与增加冠心病风险有关,并阐明了高浓度脂蛋白与冠心病之间的因果关系。相关研究成果刊登在近期的《新英格兰医学杂志》上。

由英国牛津大学休·沃特金斯教授领导的国际研究小组分析了3145例冠心病患者的样本。这些患者在66岁之前就确诊患病,并至少有一个同样患冠心病的兄弟姐妹。同时,该项研究的对照组还包括3352名健康、无冠心病家族史的志愿者。

研究人员使用基因芯片在2100个可能导致冠心病的基因中检测了48742个不同的单核苷酸多态性,最后发现有3个基因与冠心病真正相关。研究人员对其中之一的LPA基因进行了细致的研究。该基因一直被当作是一个潜在的风险基因,但到目前为止,还没有人能确切地证明哪些变种(相同等位基因)增加了冠心病的风险。

研究小组证实,在这个基因区的两个单核苷酸多态性对患病风险产生强烈影响。拥有其中一个单核苷酸多态性的患者冠心病风险会增加1.7倍;拥有另一个则会增加了1.92倍;同时拥有这两个单核苷酸多态性甚至会增加2.57倍。

不过,研究人员解释说,并不是这些单核苷酸多态性本身导致了疾病,而是他们与特定的LPA遗传变异紧密耦合并与之一起被遗传。换句话说,拥有这两个单核苷酸多态性之一的人,会有更高的可能性拥有一个LPA基因的恶意版本。

科学家们还阐明了脂蛋白(a)浓度高与冠心病之间的因果关系。脂蛋白(a),即产生于人类和一些灵长类动物肝脏的所谓Lp(a),会与血液中低密度脂蛋白(LDL)胆固醇颗粒结合。众所周知,如果Lp(a)在血液中浓度过高会导致动脉硬化、冠心病和中风。不过Lp(a)的浓度因人各异,这主要是由LPA基因的高变异性所致。

特定的基因片段,即所谓的Kringles,经常被不同地重复。Kringles的数目影响生成Lp(a)的大小,而Lp(a)越小,在血液中会积聚得越多,其导致的危害也就越大。

科学家发现,两个新确认的单核苷酸多态性通常与有19个至20个Kringles的LPA等位基因相伴。其携带者更容易在血液中含有小的Lp(a)变种,并因此有较高的Lp(a)浓度。长期令人怀疑的高Lp(a)浓度与冠心病之间的因果关系由此得到证实。(生物谷Bioon.com)

生物谷推荐原始出处:

NEJM Volume 361:2518-2528 December 24, 2009 Number 26

Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease

Robert Clarke, F.R.C.P., John F. Peden, Ph.D., Jemma C. Hopewell, Ph.D., Theodosios Kyriakou, Ph.D., Anuj Goel, M.Sc., Simon C. Heath, Ph.D., Sarah Parish, D.Phil., Simona Barlera, M.S., Maria Grazia Franzosi, Ph.D., Stephan Rust, Ph.D., Derrick Bennett, Ph.D., Angela Silveira, Ph.D., Anders Malarstig, Ph.D., Fiona R. Green, Ph.D., Mark Lathrop, Ph.D., Bruna Gigante, M.D., Karin Leander, Ph.D., Ulf de Faire, M.D., Udo Seedorf, Ph.D., Anders Hamsten, F.R.C.P., Rory Collins, F.R.C.P., Hugh Watkins, F.R.C.P., Martin Farrall, F.R.C.Path., for the PROCARDIS Consortium

Background An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood.

Methods We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects.

Results Three chromosomal regions (6q26–27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26–27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV–type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished.

Conclusions We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

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