Tanaka Toshihiro, Ozaki Kouichi
Laboratory for Cardiovascular Diseases, Research Group for Disease-Causing Mechanisms, SNP Research Center, Riken, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan.
J Hum Genet. 2006;51(7):595-604. doi: 10.1007/s10038-006-0411-8. Epub 2006 Jun 13.
Myocardial infarction (MI) is one of the common diseases whose pathogenesis includes genetic factors. To reveal genetic backgrounds of this clinically heterogeneous disorder, we started our case-control association study by examining large-scale gene-based single nucleotide polymorphism (SNP) sets for approximately 1,000 patients and controls. As a core genotyping method, a combination of multiplex PCR and Invader method was used, and after genotyping approximately 65,000 SNPs, we found two SNPs located within lymphotoxin-alpha (LTA) gene showing significant association with MI. LTA is one of the cytokines produced in the early stages of vascular inflammatory processes. These SNPs seem to be involved in inflammation by both qualitatively and quantitatively modifying the function of LTA protein, thereby conferring a risk of MI. The genetic association was further confirmed by other researchers using white European trios. To further understand the roles of LTA protein in the pathogenesis of MI, we searched for proteins that interact directly with LTA protein and identified galectin-2 protein as a binding partner of LTA protein. It is a member of galactose-binding lectin family whose function has not been well characterized. Genetic association study again revealed that an SNP in LGALS2 encoding galectin-2 was also associated with susceptibility to MI. This genetic substitution seemed to affect the transcriptional level of galectin-2, which led to altered secretion of LTA, thereby affecting the degree of inflammation. Thus, our findings indicate the importance of inflammation, especially the LTA cascade, in the pathogenesis of MI. Also, combined strategy of genetic and molecular-cellular biological approaches may be useful for clarification of the pathogenesis of common diseases in general.
心肌梗死（MI）是一种常见疾病，其发病机制包括遗传因素。为了揭示这种临床异质性疾病的遗传背景，我们通过检测大约1000例患者和对照的大规模基于基因的单核苷酸多态性（SNP）集，开展了病例对照关联研究。作为核心基因分型方法，我们使用了多重PCR和侵入法相结合的方法，在对大约65000个SNP进行基因分型后，我们发现位于淋巴毒素-α（LTA）基因内的两个SNP与MI显著相关。LTA是血管炎症过程早期产生的细胞因子之一。这些SNP似乎通过定性和定量改变LTA蛋白的功能而参与炎症反应，从而赋予MI风险。其他研究人员使用欧洲白人三联体进一步证实了这种遗传关联。为了进一步了解LTA蛋白在MI发病机制中的作用，我们寻找直接与LTA蛋白相互作用的蛋白质，并鉴定出半乳糖凝集素-2蛋白是LTA蛋白的结合伴侣。它是半乳糖结合凝集素家族的成员，其功能尚未得到很好的表征。遗传关联研究再次表明，编码半乳糖凝集素-2的LGALS2中的一个SNP也与MI易感性相关。这种基因替代似乎影响了半乳糖凝集素-2的转录水平，导致LTA分泌改变，从而影响炎症程度。因此，我们的研究结果表明炎症，尤其是LTA级联反应，在MI发病机制中的重要性。此外，遗传和分子细胞生物学方法的联合策略可能总体上有助于阐明常见疾病的发病机制。
