Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction.

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Atherosclerosis (Impact Factor: 3.97). 05/2006; 185(2):400-5. DOI: 10.1016/j.atherosclerosis.2005.06.020
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: High-risk single nucleotide polymorphisms (SNPs) have been recently identified as risk factors for ischemic heart disease in large epidemiological and genome-wide association studies. However, their influence on prognosis remains uncertain. The aim of the study was to investigate the impact of previously identified SNPs and their joint effects in a genetic score (GS) on Major Adverse Cardiac Events (MACEs). High-throughput genotyping for 48 high-risk SNPs was performed in 498 patients (432 males; 57.4 ± 8.3 years) who were followed-up for 6.9 ± 3.4 years. First MACE-coronary-related death, nonfatal myocardial infarction, or myocardial revascularization- was the endpoint taken into consideration. A GS was obtained by summing the number of significant high-risk alleles associated to MACEs. One-hundred and nineteen patients (24%) had a MACE. The hazard ratio (HR) for SNPs with a significant difference in cumulative survival were: APOC3 -482C > T (HR = 1.7, 95% CI 1.01-3.0), MTHFR (HR = 1.5, 95% CI 1.02-2.2), NADHPH oxidase- p22-PHOX C242T (HR = 1.9, 95% CI 1.2-2.8), PON-2 (HR = 0.2, 95% CI 0.1-0.8), and SELP (HR = 0.6, 95% CI 0.4-0.8). The resulting GS predicted a 25% risk for MACEs per risk allele (HR = 1.25, 95% CI 1.1-1.4, p = 0.001). The highest HR for MACEs was found in patients in the top tertile (HR = 3.0, 95% CI 1.4-6.7, p = 0.0005) of the GS compared with those in the bottom tertile. Our findings show that high-risk SNPs may be used to create a useful GS that predicts MACEs in a secondary prevention setting, which in turn allows a better risk stratification.
    Atherosclerosis 06/2012; 223(2):409-15. · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic factors have been estimated to account for about 25% of the variation in an adult's life span. The complement component C4 with the isotypes C4A and C4B is an effector protein of the immune system, and differences in the overall C4 copy number or gene size (long C4L; short C4S) may influence the strength of the immune response and disease susceptibilities. Previously, an association between C4B copy number and life span was reported for Hungarians and Icelanders, where the C4B*Q0 genotype, which is defined by C4B gene deficiency, showed a decrease in frequency with age. Additionally, one of the studies indicated that a low C4B copy number might be a genetic trait that is manifested only in the presence of the environmental risk factor "smoking". These observations prompted us to investigate the role of the C4 alleles in our large German longevity sample (∼700 cases; 94-110 years and ∼900 younger controls). No significant differences in the number of C4A, C4B and C4S were detected. Besides, the C4B*Q0 carrier state did not decrease with age, irrespective of smoking as an interacting variable. However, for C4L*Q0 a significantly different carrier frequency was observed in the cases compared with controls (cases: 5.08%; controls: 9.12%; p = 0.003). In a replication sample of 714 German cases (91-108 years) and 890 controls this result was not replicated (p = 0.14) although a similar trend of decreased C4L*Q0 carrier frequency in cases was visible (cases: 7.84%; controls: 10.00%).
    PLoS ONE 01/2014; 9(1):e86188. · 3.53 Impact Factor
  • Source
    [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-LTα(3), induced monocyte-endothelial interaction and endoplasmic reticulum (ER) stress in cardiomyocytes more strongly than the LTα(3) 804C polymorphic protein 26Thr-LTα(3). However, the effects of both LTα(3) 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-LTα(3)-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.
    Atherosclerosis 01/2013; · 3.71 Impact Factor