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Myocardial infarction (MI) results from complex interactions of multiple genetic and environmental factors. To disclose genetic backgrounds of MI, we performed a large-scale, case-control association study using 52,608 gene-based single-nucleotide polymorphism (SNP) markers, and identified a candidate SNP located on chromosome 3p21.2–p21.1. Subsequent linkage–disequilibrium mapping indicated very significant association between MI and a SNP in exon 2 of the inter-alpha (globulin) inhibitor 3 gene ( ITIH3; χ 2 = 24.88, P = 6.1 × 10−7, 3,353 affected individuals versus 3,807 controls). In vitro functional analyses showed that this SNP enhanced the transcriptional level of the ITIH3 gene. Furthermore, we found expression of the ITIH3 protein in the vascular smooth muscle cells and macrophages in the human atherosclerotic lesions, suggesting ITIH3 SNP to be a novel genetic risk factor of MI. [ABSTRACT FROM AUTHOR]

Through a large-scale case-control association study using 52,608 haplotype-based single nucleotide polymorphism (SNP) markers, we identified a susceptible locus for myocardial infarction (MI) on chromosome 22q12.1. Following linkage disequilibrium (LD) mapping, haplotype analyses revealed that six SNPs in this locus, all of which were in complete LD, showed markedly significant association with MI ( χ 2=25.27, P=0.0000005; comparison of allele frequency, 3,435 affected individuals versus 3,774 controls, in the case of intron 1 5,338 C>T; rs2331291). Within this locus, we isolated a complete cDNA of a novel gene, designated myocardial infarction associated transcript ( MIAT). MIAT has five exons, and in vitro translation assay showed that MIAT did not encode any translational product, indicating that this is likely to be a functional RNA. In vitro functional analyses revealed that the minor variant of one SNP in exon 5 increased transcriptional level of the novel gene. Moreover, unidentified nuclear protein(s) bound more intensely to risk allele than non-risk allele. These results indicate that the altered expression of MIAT by the SNP may play some role in the pathogenesis of MI. [ABSTRACT FROM AUTHOR]

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 ∼1,000 patients and controls. As a core genotyping method, a combination of multiplex PCR and Invader method was used, and after genotyping ∼65,000 SNPs, we found two SNPs located within lymphotoxin-α ( 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. [ABSTRACT FROM AUTHOR]

Galectins, a family of animal lectins that bind ß-galactoside sugar chains, are thought to have a variety of intra- and extracellular functions. Through a case-control study in the Japanese population and subsequent functional analyses, we previously showed that a functional single nucleotide polymorphism (SNP) in the gene encoding galectin-2 (lectin, galactoside-binding, soluble, 2;LGALS2) is associated with susceptibility to myocardial infarction. As an addition to the genetic information aboutLGALS2reported earlier, we provide here a map of polymorphic sites within an 11-kb region containing the gene encoding a closely related molecule, galectin-1 (lectin, galactoside-binding, soluble, 1;LGALS1). The map includes 14 SNPs and two genetic variations of other types detected in a Japanese population sample. Five of the 14 SNPs were not among those deposited in the dbSNP database in the US National Center for Biotechnology Information and appeared to be novel. We also analyzed linkage disequilibrium (LD) using the 12 SNPs in which minor-allele frequencies were>0.20. Investigation of haplotype structure within theLGALS1locus revealed five common haplotypes covering more than 95% of the test population. One, or a pair, of the SNPs described here might serve as a “tag” for detecting associations between complex diseases and genes in this local segment of chromosome 22q13.1. [ABSTRACT FROM AUTHOR]

We identified a total of 187 single-nucleotide polymorphisms (SNPs) at 11 gene loci in the 130-kb region on chromosome 6p21 containing a gene strongly associated with myocardial infarction (MI). By comparing our data with SNPs deposited in the dbSNP database at the National Center for Biotechnology Information, 46 of these SNPs (24.6%) were considered to be novel: four were identified in the P5-1 locus, 14 in the MICB locus, nine in the BAT1 locus, one in the ATP6V1G2 locus, six in the NFKBIL1 locus, one in the LTA locus, one in the TNF locus, five in the LST1 locus, four in the LY117a locus, and one in the AIF-1 locus. The SNP map presented here should provide as useful resource not only for examining the relationships between genotypes and susceptibility to the MI phenotype, but also for scanning of complex diseases mapped to this local segment on chromosome 6. [ABSTRACT FROM AUTHOR]