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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]

Abstract: Aims: We previously reported the association of single nucleotide polymorphisms in the lymphotoxin alpha (LTα) gene with susceptibility to acute myocardial infarction (AMI) and increased mortality after discharge. In the present study, we investigated whether the adverse effect of LTα C804A polymorphism on mortality could be pharmacologically modified by statin treatment after AMI. Methods and results: We conducted a multicenter study that included 3486 post-AMI patients between 1998 and 2008. During a median follow-up period of 1775 days, 247 deaths were recorded. The mortality rate was significantly higher in LTα 804A allele carriers compared to non-804A allele carriers (7.9% vs. 5.7%, p = 0.011). The LTα 804A allele was significantly associated with increased mortality for post-AMI patients not receiving statins (hazard ratio [HR]: 1.48, 95% confidence interval [CI]: 1.03–2.12, p = 0.034), but not for those receiving statins (HR: 1.22, 95% CI: 0.70–2.10, p = 0.486). In-vitro experimental analyses demonstrated that the LTα 804A polymorphic protein, 26Asn-LTα3, induced monocyte-endothelial interaction and endoplasmic reticulum (ER) stress in cardiomyocytes more strongly than the LTα3 804C polymorphic protein 26Thr-LTα3. However, the effects of both LTα3 proteins were decreased and became comparable by the pretreatment of cells with pravastatin. Conclusion: LTα C804A polymorphism was associated with an increased risk of mortality for AMI patients, although this effect was masked in patients treated with statins. This finding is supported by the observed attenuation of 26Asn-LTα3-mediated monocyte-endothelial interaction and ER stress in cardiomyocytes treated with pravastatin. LTα C804A polymorphism may have potential as a novel therapeutic target for secondary prevention after AMI. [Copyright &y& Elsevier]

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, lκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation. [ABSTRACT FROM AUTHOR]

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population. Here we identify BRAP (BRCA1-associated protein) as a galectin-2–binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 × 10−18, OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 × 10−6, 862 cases and 1,113 controls and P = 4.7 × 10−3, 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-κB, a central mediator of inflammation. [ABSTRACT FROM AUTHOR]

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]

Abstract: Although previous epidemiologic studies have suggested an association between the onset of myocardial infarction (MI) and some genetic variations, the impact of these variants on recurrent cardiovascular events after MI has not been fully elucidated. We genotyped 87 polymorphisms of 73 atherosclerosis-related genes in consecutive acute MI patients registered in the Osaka Acute Coronary Insufficiency Study and compared the incidence of death and major adverse cardiac events (MACE) among the polymorphisms of each gene. After initial screening in 507 patients, we selected nine polymorphisms for screening in all 1586 patients. Multivariate Cox regression analysis revealed that G allele carriers at the position 252 of the lymphotoxin alpha (LTA) gene were independently associated with an increased risk of death (hazard ratio [HR]: 2.46; 95% CI: 1.24–4.86). In conclusion, a 252G allele of LTA is associated with an increased risk of death after AMI and may be a useful genetic predictor. [Copyright &y& Elsevier]

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]

By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-α), NFKBIL1 (encoding nuclear factor of κ light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, χ2 = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder. [ABSTRACT FROM AUTHOR]