Early-onset Myocardial Infarction Research Articles

Hypothesis-Based Analysis of Gene-Gene Interactions and Risk of Myocardial Infarction

The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3–2.0, depending on allele frequency and interaction model).

Contribution of the TGFB1 Gene to Myocardial Infarction Susceptibility

Carriage frequencies of alleles and genotypes of the TGFB1 gene polymorphous loci -509CT (rs1800469), 869TC (rs1982073), 915GC (rs1800471), which affect the level of cytokine TGF-1 production, were analyzed in the patients of Russian ethnic descent with myocardial infarction (MI) (406 cases) and in the control group of the same ethnic descent (198 controls). Significant association with MI was observed in carriage frequencies of the allele TGFB1*-509T (p=0.046, OR =1.45, 95% CI: 1.02-2.06), genotypes TGFB1*869T/T (p=0.0024, OR =1.75, 95% CI: 1.22-2.51), and TGFB1*915G/G (p=0.048, OR=1.76, 95% CI: 1.05-2.97). Linkage disequilibrium analysis for these SNPs has shown that the associations revealed can be considered to be independent. A complex analysis of MI association with combinations of alleles/genotypes of said SNPs indicates their cumulative effect. An analysis of susceptibility to early-onset MI ( 50 years old) revealed a positive association of the allele TGFB1*-509T (p=0.002, OR=2.24, 95% CI: 1.35-3.71) and genotype TGFB1*869T/T (p=0.008, OR=1.93, 95% CI: 1.18-3.15), as well as their additivity. An analysis of susceptibility to recurrent MI revealed an association of the genotype TGFB1*-509T/T (p=0.0078, 0R=2.60, 95% CI: 1.28-5.28). The results obtained indicate the important role of the TGFB1 gene in susceptibility to MI, including early-onset and recurrent MI, in Russians.

Contribution of the TGFB1 Gene to Myocardial Infarction Susceptibility

Carriage frequencies of alleles and genotypes of theTGFB1 gene polymorphous loci -509C>T (rs1800469), 869T>C (rs1982073), 915G>C (rs1800471), which affect the level of cytokine TGF-β1 production, were analyzed in the patients of Russian ethnic descent with myocardial infarction (MI) (406 cases) and in the control group of the same ethnic descent (198 controls). Significant association with MI was observed in carriage frequencies of the alleleTGFB1*-509T (p=0.046, OR =1.45, 95% CI: 1.02-2.06), genotypes TGFB1*869T/T (p=0.0024, OR =1.75, 95% CI: 1.22-2.51), andTGFB1*915G/G (p=0.048, OR=1.76, 95% CI: 1.05-2.97). Linkage disequilibrium analysis for these SNPs has shown that the associations revealed can be considered to be independent. A complex analysis of MI association with combinations of alleles/genotypes of said SNPs indicates their cumulative effect. An analysis of susceptibility to early-onset MI (≤ 50 years old) revealed a positive association of the alleleTGFB1*-509T (p=0.002, OR=2.24, 95% CI: 1.35-3.71) and genotypeTGFB1*869T/T (p=0.008, OR=1.93, 95% CI: 1.18-3.15), as well as their additivity. An analysis of susceptibility to recurrent MI revealed an association of the genotypeTGFB1*-509T/T (p=0.0078, OR=2.60, 95% CI: 1.28-5.28). The results obtained indicate the important role of theTGFB1gene in susceptibility to MI, including early-onset and recurrent MI, in Russians.

Genetic Variant R952Q in LRP8 is Associated with Increased Plasma Triglyceride Levels in Patients with Early‐Onset CAD and MI

We previously identified a novel locus for plasma triglyceride (TG) levels on chromosome 1p31-32 by genome-wide linkage analysis in the GeneQuest population with familial and premature coronary artery disease (CAD). Here we tested a hypothesis that variants in LRP8, a gene that is under the 1p31-32 linkage peak and associated with risk of familial and premature CAD and increased platelet activation, are associated with TG levels. Seven tagSNPs that cover the entire LRP8 gene were characterized in 358 GeneQuest Caucasian probands. Only SNP R952Q (rs5174) was associated with TG levels (P-adj = 0.0016), and this finding was replicated in one other independent population of 134 patients with early-onset myocardial infarction (males <45; females <55; P-adj = 0.0098). TG levels were higher in the group with higher body mass index (BMI ≥ 25) than in the group with lower BMI (BMI < 25). The association was significant in the overweight group (P-adj = 0.0029) or in the smoking group (P-adj = 0.0004), but not in the group with normal BMI or without smoking history. These results suggest that genetic variant R952Q of LRP8 is associated with increased plasma TG levels in patients who are overweight and have premature CAD/MI and history of smoking.

Chromosome 9p21 Genetic Variants Are Associated With Myocardial Infarction But Not With Ischemic Stroke in a Taiwanese Population

BackgroundGenetic variants on chromosome 9p21 confer a robust risk for coronary artery disease but inconsistent risk for stroke. This study investigated whether such genetic variants exert differential risks on myocardial...

Influence of 9p21.3 Genetic Variants on Clinical and Angiographic Outcomes in Early-Onset Myocardial Infarction

The purpose of this study was to test whether the 9p21.3 variant rs1333040 influences the occurrence of new cardiovascular events and coronary atherosclerosis progression after early-onset myocardial infarction. 9p21.3 genetic variants are associated with ischemic heart disease, but it is not known whether they influence prognosis after an acute coronary event. Within the Italian Genetic Study of Early-onset Myocardial Infarction, we genotyped rs1333040 in 1,508 patients hospitalized for a first myocardial infarction before the age of 45 years who underwent coronary angiography without index event coronary revascularization. They were followed up for major cardiovascular events and angiographic coronary atherosclerosis progression. Over 16,599 person-years, there were 683 cardiovascular events and 492 primary endpoints: 77 cardiovascular deaths, 223 reoccurrences of myocardial infarction, and 383 coronary artery revascularizations. The rs1333040 genotype had a significant influence (p = 0.01) on the primary endpoint, with an adjusted hazard ratio of 1.19 (95% confidence interval [CI]: 1.08 to 1.37) for heterozygous carriers and 1.41 (95% CI: 1.06 to 1.87) for homozygous carriers. Analysis of the individual components of the primary endpoints provided no significant evidence that the rs1333040 genotype influenced the hazard of cardiovascular death (p = 0.24) or the reoccurrence of myocardial infarction (p = 0.57), but did provide significant evidence that it influenced on the hazard of coronary revascularization, with adjusted heterozygous and homozygous ratios of 1.38 (95% CI: 1.17 to 1.63) and 1.90 (95% CI: 1.36 to 2.65) (p = 0.00015), respectively. It also significantly influenced the angiographic endpoint of coronary atherosclerosis progression (p = 0.002). In early-onset myocardial infarction, the 9p21.3 variant rs1333040 affects the progression of coronary atherosclerosis and the probability of coronary artery revascularization during long-term follow-up.

Persistent Inflammatory Pathways Associated with Early Onset Myocardial Infarction in a Medicated Multiethnic Hawaiian Cohort

In spite of current standard therapies to target the major pathomechanisms in myocardial infarction (MI), inflammatory gene expression patterns have been consistently revealed in MI patients. In a multiethnic cohort, we aimed to identify MI-associated pathomechanisms that may be unresponsive to medical treatment to improve diagnosis and therapy. Gene expression profiles in whole blood were analyzed in medicated Asian, African American and Caucasian patients living in Hawaii with a history of early MI and age, ethnicity, risk factor and medication-matched controls. PANTHER ontological and Ingenuity Pathway analysis and functional evaluation of the consistently differentially expressed genes identified coordinated up-regulation of genes for inflammation (LGALS3, PTX3, ZBTB32, BCL2L1), T-cell activation (IL12RB1, VAV3, JAG1, CAMP), immune imbalance (IL-8, IL2RA, CCR7, AHNAK), and active atherosclerosis (NR1H4, BIN1, GSTT1, MARCO) that persist in MI patients in spite of concerted treatment efforts to control vascular pathology. Furthermore, significant ethnic differences appear to exist within the active disease mechanisms that need to be further investigated to identify key targets for effective medical intervention.

VAMP-8 gene variant is associated with increased risk of early myocardial infarction

IntroductionSingle nucleotide polymorphism in the 3’ untranslated region of the vesicle-associated membrane protein gene (VAMP-8) has been associated with increased risk of early-onset myocardial infarction (MI). In this study the risk of early onset MI conferred by VAMP-8 gene polymorphism was investigated in a group of 171 male subjects.Material and methodsMale patients with a history of MI who underwent coronary angiography were enrolled and divided into early (incident < 55 years of age) and late (incident ≥ 55 years of age) MI onset groups. Apart from the RFLP-PCR based analysis of the VAMP-8 variant, history of hypertension, lipid abnormalities, smoking and body mass index were recorded. In statistical analyses odds ratios and relative risk were used as a measure of genotype-MI association while logistic regression was implemented for evaluation of MI risk factor strength.ResultsVAMP-8 A allele frequency proved to be significantly higher in the early-onset MI group and conferred higher relative risk of early MI in the investigated cohort, when calculated for the individual A allele (p = 0.029). In logistic regression analyses no association between risk genotypes and traditional risk factors was observed.ConclusionsIn this study VAMP-8 A variant was identified as a risk allele for early MI in male subjects.

A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo1[S

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) regulates LDL cholesterol levels by inhibiting LDL receptor (LDLr)-mediated cellular LDL uptake. We have identified a fragment antigen-binding (Fab) 1D05 which binds PCSK9 with nanomolar affinity. The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wild-type PCSK9 and two gain-of-function human PCSK9 mutants, S127R and D374Y. The crystal structure of 1D05-Fab bound to PCSK9 reveals that 1D05-Fab binds to an epitope on the PCSK9 catalytic domain which includes the entire LDLr EGF(A) binding site. Notably, the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the EGF(A) domain of LDLr. In a transgenic mouse model (CETP/LDLr-hemi), in which plasma lipid and PCSK9 profiles are comparable to those of humans, 1D05-IgG2 reduces plasma LDL cholesterol to 40% and raises hepatic LDLr protein levels approximately fivefold. Similarly, in healthy rhesus monkeys, 1D05-IgG2 effectively reduced LDL cholesterol 20%-50% for over 2 weeks, despite its relatively short terminal half-life (t(1/2) = 3.2 days). Importantly, the decrease in circulating LDL cholesterol corresponds closely to the reduction in free PCSK9 levels. Together these results clearly demonstrate that the LDL-lowering effect of the neutralizing anti-PCSK9 1D05-IgG2 antibody is mediated by reducing the amount of PCSK9 that can bind to the LDLr.

Common variants in the haemostatic gene pathway contribute to risk of early-onset myocardial infarction in the Italian population

Occlusive coronary thrombus formation superimposed on an atherosclerotic plaque is the ultimate event leading to myocardial infarction (MI). Therefore, haemostatic proteins may represent important players in the pathogenesis of MI. It was the objective of this study to evaluate, in a comprehensive way, the role of haemostatic gene polymorphisms in predisposition to premature MI. A total of 810 single nucleotide polymorphisms (SNPs) in 37 genes were assessed for association with MI in a large cohort (1,670 males, 210 females) of Italian patients who suffered from an MI event before the age of 45, and an equal number of controls. Thirty-eight SNPs selected from the literature were genotyped using the SNPlex technology, whereas genotypes for the remaining 772 SNPs were extracted from a previous genome-wide association study. Genotypes were analysed by a standard case-control analysis corrected for classical cardiovascular risk factors, and by haplotype analysis. A weighted Genetic Risk Score (GRS) was calculated. Evidence for association with MI after covariate correction was found for 35 SNPs in 12 loci: F5, PROS1, F11, ITGA2, F12, F13A1, SERPINE1, PLAT, VWF, THBD, PROCR, and F9. The weighted GRS was constructed by including the top SNP for each of the 12 associated loci. The GRS distribution was significantly different between cases and controls, and subjects in the highest quintile had a 2.69-fold increased risk for MI compared with those in the lowest quintile. Our results suggest that a GRS, based on the combined effect of several risk alleles in different haemostatic genes, is associated with an increased risk of MI.

Strong association of the APOA5-1131T>C gene variant and early-onset acute myocardial infarction

BackgroundEpidemiological studies support the role for a strong genetic component in the occurrence of early-onset myocardial infarction (MI), although the specific genetic variants responsible for familial clustering remain largely unknown. MethodsThe Italian study of early-onset MI is a nationwide case-control study involving 1864 case patients <45 years old who were hospitalized for a first MI, and age/sex/place of origin-matched controls (n=1864). We investigated the association between early-onset MI, lipid levels and 20 single nucleotide polymorphisms (SNPs) in the candidate genes ADIPOQ, APOA5, ALOX5AP, CYBA, IL6, LPL, PECAM1, PLA2G2A and PLA2G7, chosen because of previously reported associations with Coronary Heart Disease (CHD) or with CHD risk factors. ResultsOf all the SNPs investigated, APOA5-1131T>C [(rs662799), minor allele frequency 0.084 (95% confidence interval (CI) 0.07–0.09)] alone showed a statistically significant association with risk of early-onset MI (p=6.7×10−5), after Bonferroni correction, with a per C allele odds ratio of 1.44 (95% CI 1.23–1.69). In controls, APOA5-1131T>C was significantly associated with raised plasma triglyceride levels (p=0.001), compared with non-carriers, the per C allele increase being 11.4% (95% CI 4–19%), equivalent to 0.15mmol/L (95% CI 0.11–0.20mmol/L). In cases, the association with early MI risk remained statistically significant after adjustment for triglycerides (p=0.006). ConclusionsThe APOA5-1131C allele, associated with higher fasting triglyceride levels, strongly affects the risk for early-onset MI, even after adjusting for triglycerides. This raises the possibility that APOA5-1131T>C may affect the risk of early MI over and above effects mediated by triglycerides.

Mitochondrial DNA and TFAM gene variation in early-onset myocardial infarction: Evidence for an association to haplogroup H

The main objective of this research was to define the association between common mitochondrial DNA (mtDNA) polymorphisms and mitochondrial transcription A gene ( TFAM) variants and myocardial infarction (MI) in patients with atherosclerotic diseased vessels. Ten mitochondrial polymorphisms that defined the nine common European haplogroups were genotyped in 500 male patients with early onset MI (< 55 years) and at least one atherosclerotic coronary vessel (angiographically confirmed), and 500 healthy controls. In addition, we searched for DNA variants in the coding region of the TFAM gene and compared patients and controls for the allele and genotype frequencies. Early onset MI was strongly associated with male gender and tobacco smoking in our population. MtDNA haplogroup H (defined by allele 7028 °C) was significantly more frequent in a first group of patients ( n = 250) compared to controls ( n = 300), and the association was confirmed in a second group of only smokers (250 patients and 200 controls). For total patients and controls, we obtained a p = 0.002 (OR = 1.50; 95% CI = 1.17–1.92) for H vs. the other haplogroups. We found four common TFAM polymorphisms, with allele/genotype frequencies that did not differ between patients and controls. In conclusion, mitochondrial haplogroup H was associated with early onset MI in male smokers. Our work supported a role for the mtDNA variation in the risk for atherosclerosis and ischemic associated events, likely due to differences in mitochondrial function and reactive oxygen production between the different haplogroups.

Familial aggregation of early-onset myocardial infarction

Background An inherited predisposition is an important factor in the etiology of myocardial infarction (MI) at a young age. However, the extent of the risk for early-onset MI in relatives of young patients is still unclear, due to the paucity of family history data. Hence familial aggregation of early-onset MI was investigated in a cohort of relatives of Italian patients who had survived MI who occurred at the age of 45 or earlier. Methods In the framework of a case–control study, lifetime data and early-onset MI status for 11,696 relatives of cases and 8897 relatives of controls were collected using a standardized questionnaire. Results Occurrence of early-onset MI in females was very uncommon (Kaplan–Meier risk = 0.6%, 95% confidence interval (CI): 0.38–0.82%, for female case relatives), and significantly lower than that for male case relatives (5.0%, 95% CI: 4.41–5.56%). The hazard ratio (HR) for case relatives was approximately 3-fold greater than that for control aunts (taken as reference category). Risk for early-onset MI to siblings (HR = 1.7, 95% CI: 1.33–2.18) was significantly different from that to parents (HR = 0.9, 95% CI: 0.71–1.16). The familial risk ratio λ R was 2.6 (95% CI: 2.30–2.89) for case relatives, using control parents as reference population for early-onset MI risk estimates (i.e. 37 per 100,000 in fathers and 7 per 100,000 in mothers). Conclusion We evaluated the risk of early-onset MI by category of relatives, obtaining evidence for familial aggregation of the disease in this Italian sample and providing figures for genetic counselling and planning genetic epidemiological studies.

Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm

We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.

Top Advances in Functional Genomics and Translational Biology for 2009

During the past years vast strides have been made in population genetics and proteomics. Genome-wide association studies (GWAS) have become large, collaborative, multicenter efforts often involving in excess of 50 000 subjects with dramatically increased power compared with previous efforts. Rapid evolution in sequencing technology has made comprehensive sequencing of the exome feasible and enabled a unique approach toward the identification of rare disease-causing variants. This year, several key proteomic articles have been published on the discovery and verification of new protein biomarkers that mark a new stage in this field, specifically in our efforts to move these emerging markers toward clinical application. The American Heart Association Functional Genomics and Translational Biology Interdisciplinary Council provides a forum for a multidisciplinary group of volunteers committed to making a substantial contribution to reduce the burden of heart disease and stroke through genetics, genomics, proteomics, and metabolomics research and translational science. On behalf of the Council on Functional Genomics and Translational Biology, we have selected 4 manuscripts published in 2009 that reflect these advances. 1. 1. Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334–341. PMID: 19198609. ### Principal Findings Most patients who have a myocardial infarction (MI) are elderly; however, a minority of patients with a MI present at an early age have a higher heritability of MI and are thus more likely to have a genetic basis for their condition. Investigators from the Myocardial Infarction Genetics Consortium1 performed a multistage case-control GWAS in subjects with early-onset MI. In an initial stage, a GWAS for single-nucleotide polymorphisms (SNPs) and copy number variants was undertaken using 2967 cases and 3075 controls. The top hits from the initial analysis and from the previously published studies were analyzed in 3 successive replication stages consisting of an …

Sterol regulatory element-binding transcription factor (SREBF)-2, SREBF cleavage-activating protein (SCAP), and premature coronary artery disease in a Chinese population

Cellular cholesterol homeostasis is controlled by the sterol-regulatory element binding transcription factors (SREBFs) that are activated by an SREBF cleavage-activating protein (SCAP). SREBF-2 1784G > C single nucleotide polymorphism (SNP, rs2228314) and SCAP 2386A > G variant (rs12487736) are associated with early onset myocardial infarction (MI) and sudden cardiac death in middle-aged men. We investigated whether these two SNPs are determinants of premature coronary artery disease (CAD) in a Chinese population. We studied 431 consecutive patients, including 197 with coronary stenosis ≥50% or previous MI and 234 controls without documented CAD (males <55 years and females <65 years). All subjects were genotyped for two SNPs by using the ligase detection reaction method. The three genotypes GG, GC, and CC were present in rs2228314 and two genotypes AA and AG in rs12487736. No gender-specific differences were found in genotype distribution and allele frequencies of these two SNPs between patients with and without CAD. The biochemical and clinical risk factors among participants were not influenced by variants at rs2228314. Logistic regression did not detect the association of these two SNPs with premature CAD, nor did there exist any association of these two SNPs among groups of patients with 0, 1, 2, and 3-vessel disease (all P > 0.05). We could not identify any association between these two SNPs and premature CAD or extent of coronary lesions in a Chinese population.

Erratum: Corrigendum: Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

Erratum: Corrigendum: Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

Genetic Variants Associated with Early Onset Myocardial Infarction also Associated with Need for Future Revascularization

A genetic variant that is associated with early-onset myocardial infarction (MI) is also associated with the progression of coronary atherosclerosis and the need for revascularization years after an MI, according to the Italian Genetic Study in Early-Onset Myocardial Infarction.

Analysis of Complex Disease Association and Linkage Studies Using the University of California Santa Cruz Genome Browser

The sequencing of the human genome, the identification of common single-nucleotide polymorphisms (SNPs) and haplotype blocks, and advances in microarray technology have enabled the study of complex diseases at a level of detail not previously imaginable. These have aided in the design and analyses of association and linkage studies of many complex diseases including cardiovascular disease. Recent technological advances have enabled the undertaking of large-scale genome-wide association studies (GWAS) that can assay hundreds of thousands of polymorphic sites on hundreds to thousands of individuals to find genomic regions associated with disease. Although results from these experiments enable the identification of smaller regions of association compared with previous studies, as with all linkage and association studies, there is the need for the further investigation of regions of interest for the causal genes or variants. The purpose of this review is to present a detailed demonstration as to how publicly available resources can be used to easily guide more detailed research into genomic regions of interest identified in linkage and association study data. Large-scale projects, such as the Human Genome Sequencing project,1,2 have generated large volumes and varieties of annotated genomic data necessitating the development of Internet-based tools to organize and make practically available these public data. One important tool in human disease research is the web-based graphical genome browsers that use the human genome sequence as the framework on which to organize genomic annotations, providing various ways for researchers to view and extract important information. Currently, there are 3 human genome browsers that have been developed for public use: (1) the National Center for Biotechnology Information (NCBI) Map Viewer3; (2) the University of California Santa Cruz (UCSC) Genome Browser4; and (3) the European Bioinformatics Institute’s Ensembl system.5 Although these genome browsers share common features and …

No influence of the VAMP8 rs1010 single nucleotide polymorphism on platelet functions in vitro

No influence of the VAMP8 rs1010 single nucleotide polymorphism on platelet functions <i>in vitro</i>