Inflammation as a risk factor for myocardial infarction.
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.
Tanaka
Toshihiro
T
Laboratory for Cardiovascular Diseases, Research Group for Disease-Causing Mechanisms, SNP Research Center, Riken, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan. toshitan@ims.u-tokyo.ac.jp
Ozaki
Kouichi
K
D016022:Case-Control Studies; D002874:Chromosome Mapping; D005091:Exons; D037501:Galectin 2 / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007438:Introns; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009203:Myocardial Infarction / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012307:Risk Factors
D037501:Galectin 2; D008233:Lymphotoxin-alpha