Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study.
Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study.
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DOI：
10.1371/journal.pgen.0020107
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发表时间：
2006-07
期刊：
影响因子：
4.5
通讯作者：
International Study of Infarct Survival (ISIS) Collaborators
中科院分区：
文献类型：
--
作者：
Clarke R;Xu P;Bennett D;Lewington S;Zondervan K;Parish S;Palmer A;Clark S;Cardon L;Peto R;Lathrop M;Collins R;International Study of Infarct Survival (ISIS) Collaborators
淋巴毒素-α(Lta)是一种促炎细胞因子，在免疫系统和局部炎症反应中发挥重要作用。LTA在动脉粥样硬化斑块中表达，与动脉粥样硬化和冠心病的发病机制有关。染色体6p21上淋巴毒素-α(Lta)基因的多态与冠心病的易感性有关，但不同的研究结果似乎相互矛盾。在国际心肌梗死存活研究(ISIS)病例对照研究中，我们研究了跨越LTA基因的七个单核苷酸多态(SNPs)及其相关单倍型与心肌梗死(MI)风险的关系。这7个SNPs(包括rs909253和rs1041981 SNPs)相互之间存在很强的连锁不平衡，导致了6种常见的单倍型。部分LTA单倍型与较高的C反应蛋白浓度(p=0.004)和较低的白蛋白浓度(p=0.023)相关。然而，SNPs或相关单倍型与心肌梗死的风险均无显著关联。ISIS研究的结果是在先前发表的六项评估这种相关性的研究的背景下进行考虑的，这项荟萃分析使用隐性模型发现与冠心病风险没有显著关联，使用显性模型仅发现适度的关联(围绕这些风险估计的狭窄可信区间)。总体而言，这些研究提供了可靠的证据，表明LTA基因的这些常见多态与冠状动脉疾病的易感性没有很强的关联。淋巴毒素-α基因(Lta)编码一种参与免疫系统的细胞因子，该因子与冠心病的风险有关。在最早的全基因组关联研究中，一个日本研究小组报告说，LTA基因的多态与患冠心病的风险增加1.8倍有关。这篇论文的作者在一项病例对照研究中检查了LTA基因的几种多态与CHD风险的关系，该研究涉及英国6928名心脏病发作幸存者和2712名无关对照。LTA基因的多态性(包括最初的日本研究中检测到的那些)均与冠心病风险无关。此外，一项对所有已发表研究的荟萃分析发现，LTA与冠心病风险之间没有显著的关联。这些发现强调，大规模研究需要有足够的能力来发现遗传变异与冠心病风险的关联，并需要在更大规模的独立研究中复制任何此类关联。
Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease. Lymphotoxin-α gene (LTA) encodes a cytokine involved in the immune system that has been linked with risk of coronary heart disease (CHD). In one of the first genome-wide association studies, a Japanese group reported that polymorphisms for the LTA gene were associated with a 1.8-fold higher risk of CHD. The authors of this current paper examined associations of several polymorphisms for the LTA gene with risk of CHD in a case-control study of 6,928 heart attack survivors and 2,712 unrelated controls in the United Kingdom. None of the polymorphisms for LTA (including those examined in the original Japanese study) were associated with CHD risk. Moreover, a meta-analysis of all published studies found no significant association of LTA with CHD risk. These findings emphasize the need for large-scale studies to have sufficient power to detect associations of genetic variants with CHD risk and the need for replication of any such associations in independent studies of even larger size.
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