Project description:ObjectiveThe rs10757278, rs1333049 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus associated with a prevalence of acute coronary syndromes (ACS). Reports concerning their association with long-term outcome after an ACS are equivocal. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI).Materials and methodsWe performed a retrospective analysis of data collected prospectively in 2 independent registries of consecutive patients with STEMI (derivation and validation group). Genotyping was performed with the TaqMan method. The analyzed end-point was total mortality.ResultsThe derivation group comprised 589 patients: 25.3% female (n = 149), mean age 62.4 ± 12.0 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (GRACE risk score ≥ 155 points, n = 238), homozygotes associated with higher risk for ACS had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with the high-risk genotype (a homozygote of high risk for ACS or a heterozygote) was: HR = 2.2 (1.15-4.2) for the rs10757278 polymorphism, HR = 2.7 (95% CI 1.3-5.4) for the rs4977574 one and HR = 2.3 (1.2-4.5) for the rs1333049 one (Cox proportional hazards model). Survival analysis in the validation group (n = 365) showed a clear trend towards better prognosis in GG homozygotes of the rs10757278 SNP, which confirms our initial results (p = 0.09, log-rank test).ConclusionsThe 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. The genotypes associated with higher risk for ACS show a protective effect in terms of further survival (instead of a deteriorating prognosis, as reported previously). This finding, due to the very high size of the effect, could potentially be applied to clinical practice, if appropriate methods are elaborated.
Project description:ObjectiveThe rs1333049, rs10757278 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus that are associated with prevalence of acute coronary syndromes (ACS). The rs1333049 SNP was also associated with cardiac outcome 6 months post ACS. No data concerning their association with long term prognosis after myocardial infarction is available. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI) treated invasively.Materials and methodsWe performed a retrospective analysis of data collected prospectively in a registry of consecutive patients with STEMI treated with primary PCI. Genotyping was performed with a TaqMan method. The analyzed end-point was total 5-year mortality.ResultsThe study group comprised 589 patients: 25.3% of females (n = 149), mean age 62.4±11.9 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (Grace risk score ≥155 points, n = 238), low-risk homozygotes had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with high-risk genotype (high-risk homozygote or heterozygote) was: HR = 2.9 (95%CI 1.4-6.1) for the rs4977574 polymorphism, HR = 2.6 (1.25-5.3) for the rs1333049 one and HR = 2.35 (1.2-4.6) for the rs10757278 one (Cox proportional hazards model).ConclusionsThe 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. This finding, due to very high effect size, could potentially be applied into clinical practice, if appropriate methods are elaborated.
Project description:Background: Previous genome-wide association studies revealed that the chromosome 9p21.3 locus is associated with an increased risk of myocardial infarction (MI) and diabetes mellitus (DM). However, it is unclear whether the 9p21.3-MI association is direct or mediated by pathways related to DM. Study Design: We applied mediation analysis to examine the potential mediating effect of DM on the association between the 9p21.3 genetic risk score (GRS; ranged from 0 to 8) and MI in a case-control study of 865 MI patients and 927 controls without coronary artery disease (CAD). The GRS combining 4 lead 9p21.3 single nucleotide polymorphisms (rs1333040, rs4987574, rs2383207, and rs1333049) was constructed. Results: Each 1 unit increase in weighted 9p21.3 GRS was associated with a 9% increased DM risk (95% confidence interval (CI) 1.00, 1.19) in the control group and a 14% increased MI risk (95% CI 1.09, 1.20). Mediation analyses yielded a direct-effect odds ratio (OR) of 1.06 (95% CI 1.04, 1.08) and an indirect-effect OR of 1.00 (95% CI 0.99, 1.01) for weighted GRS. DM mediated 4.40% (95% CI 3.42, 6.52) of the total association between the weighted GRS and MI risk. Individuals with the highest quartile of 9p21.3 GRS and DM had a 6-fold higher MI risk than those with the lowest quartile of 9p21.3 GRS and non-DM (OR 6.03, 95% CI 3.48, 10.5). Conclusion: DM is a weak mediator that explains a small fraction of the 9p21. 3-MI association in Chinese adults. Nevertheless, there is a strong synergistic effect between DM and the 9p21.3 GRS on MI risk.
Project description:The 9p21.3 risk locus is the first locus to be associated with an increased risk of coronary artery disease (CAD)-related events and many other phenotypes. This locus contains 59 single nucleotide polymorphisms (SNPs) in a region with multiple long range enhancers and long non-coding RNAs (lncRNAs) that affect the expression of neighbouring genes, cyclin-dependent kinase 2A and 2B (CDKN2A and CDKN2B), which are required for controlling vascular smooth muscle cell proliferation and ageing. Several studies have attempted to identify the precise mechanism by which this locus exerts its pathogenic effect to increase the risk of CAD-related events. In this review, we will highlight the major advances in our understanding of the genotype-phenotype correlation at the mechanistic and phenotypic levels. The high population attributable risk of the 9p21.3 risk locus, mechanistic knowledge acquired thus far, and ongoing research efforts could facilitate the design of novel therapeutic molecules to reduce the risk of CAD and its related events.
Project description:Acute myocardial infarction (AMI) is a major health concern in India. The aim of the study was to identify single nucleotide polymorphisms (SNPs) associated with AMI in patients using dedicated chip and validating the identified SNPs on custom-designed chips using high-throughput microarray analysis.In pilot phase, 48 AMI patients and 48 healthy controls were screened for SNPs using human CVD55K BeadChip with 48,472 SNP probes on Illumina high-throughput microarray platform. The identified SNPs were validated by genotyping additional 160 patients and 179 controls using custom-made Illumina VeraCode GoldenGate Genotyping Assay. Analysis was carried out using PLINK software.From the pilot phase, 98 SNPs present on 94 genes were identified with increased risk of AMI (odds ratio of 1.84-8.85, P=0.04861-0.003337). Five of these SNPs demonstrated association with AMI in the validation phase (P=0.05). Among these, one SNP rs9978223 on interferon gamma receptor 2 [IFNGR2, interferon (IFN)-gamma transducer 1] gene showed a significant association (P=0.00021) with AMI below Bonferroni corrected P value (P=0.00061). IFNGR2 is the second subunit of the receptor for IFN-gamma, an important cytokine in inflammatory reactions.The study identified an SNP rs9978223 on IFNGR2 gene, associated with increased risk in AMI patient from India.
Project description:ObjectiveST-segment myocardial infarction (STEMI) is a time-sensitive emergency. This study screened the favorable factors for the survival of STEMI patients with medium- and high-risk thrombolysis in myocardial infarction (TIMI) scores.MethodsAccording to the TIMI scores at admission, 433 STEMI patients were retrospectively and consecutively selected and allocated into low-/medium-/high-risk groups, with their general information/blood routine/biochemical indicators/coagulation indicators documented. The factors influencing the in-hospital survival of STEMI patients were analyzed using univariate and multivariate logistic regression analyses. Moreover, the predictive value of favorable factors was analyzed by receiver operating characteristics (ROC) curve, and patients were assigned into high/low level groups based on the cut-off value of these factors, with their in-hospital survival rates compared.ResultsThe in-hospital survival rate of the medium-/high-risk groups was lower than that of the low-risk group. Emergency percutaneous coronary intervention (PCI), lymphocyte (LYM), total protein (TP), albumin (ALB), and sodium (Na) were independent favorable factors for in-hospital survival in the medium-/high-risk groups. Besides, LYM > 1.275 × 109/L, TP > 60.25 g/L, ALB > 34.55 g/L, and Na > 137.9 mmo1/L had auxiliary predictive value for the survival of STEMI patients with medium-/high-risk TIMI scores. Patients with high levels of LYM, TP, ALB, and Na exhibited higher in-hospital survival rates than patients with low levels.ConclusionFor STEMI patients with medium- and high-risk TIMI scores, accepting emergency PCI and normal levels of LYM, TP, ALB, and Na were more conducive to in-hospital survival.
Project description:The rs1333049 (G/C) polymorphism located on chromosome 9p21.3 is a candidate to influence extreme longevity owing to its association with age-related diseases, notably coronary artery disease (CAD). We compared allele/genotype distributions of rs1333049 in cases (centenarians) and controls (younger adults, without (healthy) or with CAD) in two independent cohorts: Spanish (centenarians: n?=?152, 128 women, 100-111 years; healthy controls: n?=?343, 212 women, age <50 years; CAD controls: n?=?98, 32 women, age ?65 years) and Japanese (centenarians: n?=?742, 623 women, 100-115 years; healthy controls: n?=?920, 511 women, < 60 years; CAD controls: n?=?395, 45 women, age ?65 years). The frequency of the "risk" C-allele tended to be lower in Spanish centenarians (47.0 %) than in their healthy (52.9 %, P?=?0.088) or CAD controls (55.1 %, P?=?0.078), and significant differences were found in genotype distributions (P?=?0.034 and P?=?0.045), with a higher frequency of the GG genotype in cases than in both healthy and CAD controls as well as a lower proportion of the CG genotype compared with healthy controls. In the Japanese cohort, the main finding was that the frequency of the C-allele did not differ between centenarians (46.4 %) and healthy controls (47.3 %, P?=?0.602), but it was significantly lower in the former than in CAD controls (57.2 %, P?<?0.001). Although more research is needed, the present and recent pioneer findings (Rejuvenation Res 13:23-26, 2010) suggest that the rs1333049 polymorphism could be among the genetic contributors to exceptional longevity in Southern European populations, albeit this association does not exist in the healthy (CAD-free) Japanese population.
Project description:BACKGROUND: Abnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI. METHODS: Genotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR?=?1.62, P?=?0.039) and the combined CT/CC genotype (OR?=?1.67, P?=?0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (?60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects. CONCLUSIONS: Our data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels.
Project description:Genetic factors contribute to about a half of coronary artery diseases. During the last several decades, some studies suggested that non-O blood group and thrombomodulin polymorphism -33G>A are the risk factors of coronary artery disease especially in Asia. There was no prior study in Indonesia regarding this issue. Hence, this study was designed to investigate the correlation of ABO polymorphism and thrombomodulin polymorphism -33G>A with the incidence of acute myocardial infarction (AMI). A total of 192 subjects were enrolled in this case control study. AMI patients were diagnosed based on World Health Organization criteria. Healthy patients were subjects with AMI risk factor without any sign and symptoms of AMI. Patients with diabetes mellitus, cancer, and arrhythmia were excluded from this study. Genotyping for both polymorphisms was performed by PCR RFLP methods. The result of this study suggested that ABO polymorphism and thrombomodulin polymorphism -33G>A were not risk factors of AMI, p = 0.727 and p = 0.699, respectively. Furthermore, the analysis to identify the synergy of these polymorphisms failed to prove their correlation with AMI (p = 0.118). Conclusively, this study showed that ABO polymorphism and thrombomodulin polymorphism -33G>A were not risk factors of AMI.
Project description:Risk stratification plays a key role in identifying acute myocardial infarction (AMI) patients at higher risk of mortality. However, current AMI risk scores such as the Global Registry of Acute Coronary Events (GRACE) score were derived from predominantly Caucasian populations and may not be applicable to Asian populations. We previously developed an AMI risk score from the national-level Singapore Myocardial Infarction Registry (SMIR) confined to ST-segment elevation myocardial infarction (STEMI) patients and did not include non-STEMI (NSTEMI) patients. Here, we derived a modified SMIR risk score for both STEMI and NSTEMI patients and compared its performance to the GRACE 2.0 score for predicting 1-year all-cause mortality in our multi-ethnic population. The most significant predictor of 1-year all-cause mortality in our population using the GRACE 2.0 score was cardiopulmonary resuscitation on admission (adjusted hazards ratio [HR] 6.50), while the most significant predictor using the SMIR score was age 80-89 years (adjusted HR 7.78). Although the variables used in the GRACE 2.0 score and SMIR score were not exactly the same, the c-statistics for 1-year all-cause mortality were similar between the two scores (GRACE 2.0 0.841 and SMIR 0.865). In conclusion, we have shown that in a multi-ethnic Asian AMI population undergoing PCI, the SMIR score performed as well as the GRACE 2.0 score.