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.
", we enrolled 3486 patients who were discharged alive and submitted samples for the genetic analysis performed in this study. Details of the OACIS and genotyping have been reported elsewhere  . All patients provided written informed consent, and the study protocol complied with the Guidelines for Genome/Genetic Research issued by the Japanese government and was approved by the ethics committee of each institution. "
[Show abstract][Hide abstract] 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.
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.
"Several million single nucleotide polymorphisms (SNPs) have been identified and genome-wide maps of SNP are available. These resources, together with platforms for massive SNP genotyping, have rendered genome-wide association studies feasible for diseases such as diabetes mellitus (Saxena et al., 2007), myocardial infarction (Mizuno et al., 2006), cancer (Gudmundsson et al., 2007), inflammatory bowel disease (Xavier and Podolsky, 2007). Other techniques, like the two-hybrid screening (also known as yeast two-hybrid system or Y2H), allow massive analysis of protein–protein interactions or protein– DNA interactions (for DNA-binding proteins , such as transcription factors). "
"Lymphotoxin-alpha (LTA), a cytokine affecting proinflammatory processes, is a factor promoting the development of atherosclerosis        . The LTA gene has been implicated in the pathomechanism of ischemic stroke and myocardial infarction, the LTA 252GG homozygote, which naturally coexists with the 804AA homozygote, has also been demonstrated to contribute to myocardial infarction or large-vessel-associated ischemic stroke      . In consistence with these observations, a recent article demonstrated that the LTA 252GG homozygote variant is associated with an increased intima-media thickness in the carotid arteries . "
[Show abstract][Hide abstract] ABSTRACT: The galectin-2 protein is presumed to play a regulatory role in the intracellular trafficking of the lymphotoxin-alpha (LTA) cytokine. LTA is a pro-inflammatory factor, its 252GG homozygote variant is considered as a susceptibility factor for arteriosclerosis and cardiovascular diseases. By contrast, the galectin-2-encoding gene LGALS2 3279TT homozygote variant has been demonstrated to exert protection against myocardial infarction by reducing the transcriptional level of galectin-2, thereby leading to a reduced extracellular secretion of LTA.
In the present study, we examined whether the LGALS2 3279TT homozygote variant alone can influence the prevalence of ischaemic stroke, and whether it can interact somehow with the disadvantageous LTA 252GG homozygote variant. Genetic and clinical data of 385 ischemic stroke patients and 303 stroke and neuroimaging alteration-free controls were analysed.
The combination of the LGALS2 3279TT and LTA 252GG homozygote was significantly less frequent in the ischemic stroke group (1.56%) than in the controls (5.94%, p<0.00187; overall stroke group: crude OR: 0.25, 95% CI: 0.1-0.64; adjusted OR: 0.03, 95% CI: 0.025-0.71).
This finding suggests a gene-gene interaction.
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