Genetic Risk Factor For Coronary Artery Disease Research Articles

Abstract 18686: Distinct Proteomic Signatures in Subjects With Elevated Lipoprotein(a) Levels With and Without Coronary Artery Disease

Introduction: Genetic and observational studies suggest a causal link between an elevated lipoprotein(a) [Lp(a)] and coronary artery disease (CAD). Although Lp(a) is one of the strongest genetic risk factors for CAD, not all subjects with an elevated Lp(a) develop CAD. Hypothesis: We hypothesized that in subjects with an elevated Lp(a) (>150nmol/L), proteomic signatures could differentiate between those with and without CAD. Methods: Outpatients with known Lp(a) levels and a coronary CT between April 2021 to April 2023 were enrolled and circulating biomarkers were measured using Olink proteomic platform. This study was approved by the IRB at the Icahn School of Medicine, New York, NY. Results: First we analyzed clinical markers and proteomic signatures in subjects with and without CAD. An elevated Lp(a) level was a critical feature between the two groups. We then focused our analysis on differences in clinical and proteomic signatures in subjects with an elevated Lp(a). High Lp(a) subjects with (n=28) and without CAD (n=7) were well matched with respect to clinical characteristics including age (66 vs 52y; NS) and median Lp(a) levels (228; [203-270] vs 222; [204-323]). Additionally, hsCRP and LDL-C levels were well matched between groups. 2907 unique proteomic markers were detected and there were 29 markers that were significantly different in high Lp(a) subjects with CAD compared with those without CAD. An unsupervised principal component analysis was performed, and we found that markers of thrombosis (PARP1, tissue factor), inflammation (CCL3, CD40) were key proteomic markers that separated high Lp(a) subjects with and without CAD, suggesting a bidirectional relationship between inflammatory and thrombotic pathways in Lp(a)-driven CAD. Conclusions: To our knowledge, this is the first prospective study to examine proteomic differences in high Lp(a) subjects with and without CAD. Profiling over 3000 unique proteomic markers, we found that in high Lp(a) subjects, there were differences in thrombotic and inflammatory markers in those with CAD compared to those without CAD. These findings have important implications to understanding the mechanisms through which Lp(a) drives CAD and in risk stratifying high Lp(a) subjects susceptible to CAD.

THE INVESTIGATION OF LIPOPROTEIN-RELATED PHOSFOLIPASE A2 (LP-PLA2) V279F MUTATION IN CORONARY ARTERY DISEASE

Objective: Despite advances in the treatment of cardiovascular diseases, coronary artery disease (CAD) maintains to be the leading cause of death in many nations. The media layer of normal and diseased arteries contains lipoprotein-associated phospholipase A2 (Lp-PLA2), which is mostly made by mast, T lymphocytes, and monocytes. Our research sought to define how the Lp-PLA2 and V279F gene polymorphisms relate to CAD. Materials and Methods: This study included 71 controls and 109 patients. Fasting blood glucose (FBG) and lipid profiles, were measured the enzymatic colorimetric technique. Lp-PLA2 levels were detected with ELISA. The genomic DNAs were isolated from whole blood. Real-time polymerase chain reaction (RT-PCR) with the V279F mutation detection kit was used to identify the Lp-PLA2 V279F mutation. Results: In the CAD compared to the controls, serum Lp-PLA2 levels were higher (p 0.001). While FF (mutant) genotypes and VF (heterozygous) genotypes were absent from both groups, the Lp-PLA2 V279F mutation was discovered as the VV (wild) genotype in both control and CAD. Conclusion: As a result, we determined that the Lp-PLA2 V279F mutation cannot be considered a genetic risk factor for CAD, but that Lp-PLA2 elevation may be an important parameter for CAD.

Common gene polymorphism in ATP-binding cassette transporter A1 and coronary artery disease: A genetic association study and a structural analysis.

ATP-binding cassette transporter A1 (ABCA1) has a crucial role in removing intracellular cholesterol and plays a protective role against atherosclerosis. Therefore, genetic polymorphisms in this gene may alter the susceptibility to coronary artery disease (CAD). This study was aimed to examine the association of rs2230806 (c.1051 G > A; p.R219K) variation in the ABCA1 gene with CAD in a case-control design which was followed by a meta-analysis and in silico approach. In the case-control study, 300 subjects including 150 individuals with CAD and 150 healthy controls were recruited. The c.1051 G > A genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method. In the meta-analysis, eligible studies were collected from PubMed, Google Scholar, and ScienceDirect databases and pooled odds ratio, heterogeneity, publication bias, and sensitivity analyses were carried. Finally, some bioinformatics tools were employed to assess the impacts of p.R219K variation on ABCA1 protein structure. Our case-control examination showed a statistically significant association between c.1051 G > A genetic polymorphism and CAD risk. In addition, the meta-analysis showed reliable significant associations between c.1051 G > A transition and risk of CAD in the Caucasian population. In silico analysis showed that the p.R219K substitution could alter the secondary structure, hydrophobicity pattern, and Ramachandran plot of ABCA1. These findings elucidate that the c.1051 G > A variation could be a genetic risk factor for CAD and it could be considered as a prognostic and predictive biomarker for susceptible individuals.

Abstract 021: ARHGEF26 is a Novel Genetic Risk Factor for Vascular Inflammation and Coronary Artery Disease

Vascular inflammation drives the initiation and progression of coronary artery disease (CAD). However, the underlying genetic factors are not well understood. We performed a genome-wide association study in UK Biobank testing 9 million DNA variants for association with CAD (4,831 cases, 115,455 controls), followed by a meta-analysis with previous results. We identified ARHGEF26 (Rho guanine nucleotide exchange factor 26) as a novel locus significantly associated with CAD (combined OR=1.08, 95% CI 1.06-1.11, P=1.02 х 10 –9 ). We hypothesized that ARHGEF26 regulates vascular inflammation by affecting the function of vascular cells. Focusing on the haplotype tagged by the lead variant rs12493885 (ARHGEF26 p.Val29Leu), we performed eQTL and allele-specific expression analyses. There is no significant ARHGEF26 transcription alteration or allelic imbalance associated with the risk allele in human coronary artery samples. Promoter luciferase assay showed no significant difference between the reference and alternative haplotypes. In contrast, expression of exogenous Leu29 mutant after depletion of endogenous ARHGEF26 led to rescued phenotypes consistently exceeding those observed with overexpression of wild-type ARHGEF26, including increased leukocyte transendothelial migration, leukocyte adhesion on endothelial cells, and smooth muscle cell proliferation. These data suggest that the CAD-risk allele (Leu29) may lead to a gain of protein function in vascular cells. To identify the molecular mechanism, we compared the nucleotide-exchange activity between the wild-type and mutant proteins and found no significant difference. Evaluation of ARHGEF26 protein stability by cycloheximide chase showed the Leu29 mutant displayed longer half-life than wild-type ARHGEF26, suggesting the gain-of-function phenotypes of Leu29 in cells may be secondary to its resistance to degradation. Quantitative proteomics revealed differential protein interaction between the wild-type and Leu29 ARHGEF26 in endothelial cells, highlighting critical inflammatory pathways impacted by the CAD-risk allele. In summary, our work identified a novel genetic risk factor for CAD, and enabled discovery of novel CAD-causing pathways in vascular inflammation.

Association of the HNF1A polymorphisms and serum lipid traits, the risk of coronary artery disease and ischemic stroke.

BackgroundHepatocyte nuclear factor‐1α gene (HNF1A) single nucleotide polymorphisms (SNPs) have been associated with serum lipid traits in several previous genome‐wide association studies. However, little is known about such associations in the Chinese populations. The present study aimed to determine the association of the HNF1A rs1169288, rs2259820, rs2464196 and rs2650000 SNPs and serum lipid traits, the risk of coronary artery disease (CAD) and ischemic stroke (IS).MethodsThe genotypes of the four SNPs in 562 CAD and 521 IS patients, as well as 594 healthy controls, were detected using the Snapshot technology.ResultsThe genotype and allele distribution of the four SNPs was not different between controls and CAD or IS patients (p > 0.05 for all). rs1169288, rs2259820 and rs2464196 SNPs were significantly associated with serum lipid levels in both controls and CAD patients (p < 0.004–0.009). rs2259820 and rs2464196 SNPs were significantly associated with a lower risk of CAD [odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.44–0.91, p = 0.015 and OR =0.62, 95% CI = 0.43–0.89, p = 0.010, respectively]. Significant linkage disequilibrium was noted among the four SNPs (r 2 > 0.5, D′ > 0.8). The haplotype of rs1169288A‐rs2259820C‐rs2464196G‐rs2650000A was associated with an increased risk of CAD (OR =1.95, 95% CI: 1.13–3.37, p = 0.015). Interactions of SNP–SNP (rs1169288–rs2464196–rs2650000) and haplotype–environment on the risk of CAD (A‐C‐G‐A–smoking) or IS (A‐C‐G‐A–sex and A‐T‐A‐C–alcohol consumption) were also observed among these SNPs.ConclusionsThese findings suggest that the HNF1A polymorphisms may be the genetic risk factors for CAD and IS.

Rs10887800 renalase gene polymorphism is associated with an increased risk of coronary artery disease in hemodialyzed patients.

PurposeCoronary artery disease (CAD) is common in patients with end-stage renal disease (ESRD). Recent studies have suggested that renalase, a novel FAD-dependent amine oxidase, may play an important role in the pathogenesis of cardiovascular complications in ESRD patients. The aim of the study was to investigate the association between renalase gene polymorphisms and a risk of CAD in patients on hemodialysis.MethodsIn a case–control study, a total of 309 hemodialyzed patients (107 with and 202 without CAD) were genotyped for two SNPs in the renalase gene (rs10887800 and rs2576178) using the PCR–RFLP method.ResultsBy multivariate logistic regression analysis, we found that rs10887800GG genotype was associated with an increased risk of CAD under the codominant model [GG vs AA; adjusted OR 2.66 (95 % CI, 1.19–5.94), p = .017] and under the recessive model [GG vs AG + AA; adjusted OR 2.10 (95 % CI, 1.10–4.02), p = .025]. The rs2576178 polymorphism did not influence the risk of CAD.ConclusionThe study suggested for the first time that the rs10887800 renalase gene polymorphism may be involved in the pathogenesis of CAD in hemodialyzed patients and thus could be considered a new genetic risk factor for CAD in this population.

Exome-Wide Association Analysis of Coronary Artery Disease in the Kingdom of Saudi Arabia Population.

Coronary Artery Disease (CAD) remains the leading cause of mortality worldwide. Mortality rates associated with CAD have shown an exceptional increase particularly in fast developing economies like the Kingdom of Saudi Arabia (KSA). Over the past twenty years, CAD has become the leading cause of death in KSA and has reached epidemic proportions. This rise is undoubtedly caused by fast urbanization that is associated with a life-style that promotes CAD. However, the question remains whether genetics play a significant role and whether genetic susceptibility is increased in KSA compared to the well-studied Western European populations. Therefore, we performed an Exome-wide association study (EWAS) in 832 patients and 1,076 controls of Saudi Arabian origin to test whether population specific, strong genetic risk factors for CAD exist, or whether the polygenic risk score for known genetic risk factors for CAD, lipids, and Type 2 Diabetes show evidence for an enriched genetic burden. Our results do not show significant associations for a single genetic locus. However, the heritability estimate for CAD for this population was high (h2 = 0.53, S.E. = 0.1, p = 4e-12) and we observed a significant association of the polygenic risk score for CAD that demonstrates that the population of KSA, at least in part, shares the genetic risk associated to CAD in Western populations.

Common genetic risk factors for coronary artery disease: new opportunities for prevention?

Atherosclerotic cardiovascular disease (CVD) is a leading cause of mortality and morbidity worldwide, with coronary artery disease (CAD) being the single leading cause of death. Better control of risk factors, enhanced diagnostic techniques and improved medical therapies have all substantially decreased the mortality of CAD in developed countries. However, CAD and other forms of atherosclerotic CVD are projected to remain the leading cause of death by 2030 and we face a number of challenges if the outcomes of CAD are to be further improved. The fact that a substantial fraction of high-risk subjects do not reach treatment goals for important risk factors is one of these challenges. At the same time, there is also a non-negotiable fraction of 'concealed' high-risk subjects who are not detected by current risk algorithms and diagnostic modalities. In recent years, we have started to rapidly increase our knowledge of the framework of common genetics underlying CAD and atherosclerotic CVD in the population. In conjunction with modern diagnostic and therapeutic options, this new genetic knowledge may provide a valuable tool for further improvements in prevention. This review summarizes the recent findings from the search for common genetic risk factors for CAD. Furthermore, the author discusses how such recent findings could potentially be used in a number of clinical applications within CAD prevention, including in clinical risk stratification, in prediction of drug treatment response and in the search for targets for novel preventive therapies.

Double trouble: T2DM genetic risk factors play a causal role in CAD.

Double trouble: T2DM genetic risk factors play a causal role in CAD.

Chemokine CX3CL1 and its receptor CX3CR1 are associated with human atherosclerotic lesion volnerability

BackgroundCX3CL1 and its receptor CX3CR1 have been emphasized in atherosclerosis recently. In this study we investigated the role of the chemokines CX3CL1 and their receptor CX3CR1 in atherogenesis and identified whether the genetic variations in CX3CL1 and CX3CR1 impacted the atherosclerosis process in coronary artery disease (CAD) or not. MethodsCX3CL1/CX3CR1 expression in coronary and carotid artery specimens were analysed by immunohistochemistry. CX3CR1 expression on CD4+ CD28- T cells was analysed by flow cytometry. We also screened for CX3CL1/CX3CR1 sequence variations selected from the hapmap database and examined the association between CX3CL1/CX3CR1 and CAD in the Chinese Han population. ResultsImmunohistochemical staining of tissue from CAD patients showed increased CX3CL1/CX3CR1 expression in atherosclerotic coronary and carotid artery plaques compared with normal arteries. CX3CL1/CX3CR1 expression was correlated with the severity of the atherosclerosis lesion. Patients with CAD also showed an increased number of CX3CR1+ CD4+ CD28- T cells. Compared with their corresponding wild-type genotypes, CX3CL1 rs170364 and CX3CR1 rs17793056 were associated with increased susceptibility to CAD. ConclusionsCX3CL1 and CX3CR1 may contribute to the formation of coronary atherosclerotic plaque in CAD.CX3CL1 rs170364 and CX3CR1 rs17793056 polymorphisms may be independent genetic risk factors for CAD.

The Kalirin Gene rs9289231 Polymorphism as a Novel Predisposing Marker for Coronary Artery Disease.

Atherosclerosis is the leading cause of death and disability worldwide. Genetic variations play a major role in the process of atherosclerosis. Recently, rs9289231 genetic variations of the Kalirin gene (KALRN) on chromosome 3q21.2 have been introduced as potential genetic markers for coronary artery disease (CAD). In this case-control study, we investigated the association between genetic susceptibility to CAD and rs9289231 G/T polymorphism, located on the KALRN gene, in an Iranian population. Our cohort consisted of 1486 individuals undergoing coronary angiography. Of these, we considered the 1007 patients with CAD to be case individuals and the 479 individuals with normal coronary conditions to be control individuals. We performed single-nucleotide polymorphism (SNP) genotyping via the high resolution melting (HRM) technique. Our data showed that the minor allele (G) frequency of rs9289231 SNP was higher in our CAD group than that in our control group (odds ratio, 1:37; confidence interval, 1.07-1.74; P = .01). The results of our data analysis highlighted a genetic association between rs9289231 polymorphism and severity and development of CAD. We consider the GG genotype and the G allele of rs9289231 polymorphism of KALRN to be genetic risk factors for CAD in an Iranian population, especially in early-stage atherosclerotic vascular disease.

Meta-analysis identifies robust association between SNP rs17465637 in MIA3 on chromosome 1q41 and coronary artery disease

Several large-scale meta-GWAS identified significant association between SNP rs17465637 in the MIA3 gene and coronary artery disease (CAD) in the European ancestry populations. However, three follow-up replication studies in the Chinese populations yielded inconsistent results. In order to unequivocally determine whether SNP rs17465637 is associated with CAD, we performed an independent case control association study in the Chinese Han population and a follow-up large scale meta-analysis for SNP rs17465637. Our study included 2503 CAD patients and 2920 non-CAD controls of the Chinese Han origin. A significant association was found between SNP rs17465637 and CAD (P = 0.01, OR = 1.11). Meta-analysis included 7263 CAD patients and 8347 controls combined from five Asian populations. The association between SNP rs17465637 and CAD became highly significant (P = 4.97 × 10−5, OR = 1.11). Similar analysis also identified significant association between SNP rs17465637 and MI (2424 cases vs. 6,536controls; P = 5.00 × 10−3, OR = 1.10). We conclude that SNP rs17465637 in MIA3 is indeed a genetic risk factor for CAD across different ethnic populations.

Gender specificity of a genetic variant of angiotensin-converting enzyme and risk of coronary artery disease

Etiological factors for coronary artery disease (CAD) involve a wide range of gene and environmental interactions. One of the systems being implicated in the pathophysiology of CAD is the renin-angiotensin system (RAS). However, the genetic polymorphisms of this system have not been widely studied in Iranian patients diagnosed with CAD. The aim of this study was to assess the relationship between six gene polymorphisms of RAS components and CAD in a sample of Iranian population. A total of 374 participants were enrolled in a case/control study. The presence of CAD was determined by coronary angiography. Genotyping of six RAS gene polymorphisms was performed using a modified PCR-RFLP method. Our results revealed, for the first time, a significant independent association of angiotensin-converting enzyme (ACE) A-240T polymorphism and incidence of CAD among Iranian women (P=0.005, OR=20.4, 95% CI=2.49-41.2). There has also been a significant difference in genotype distribution of ACE A-240T (P=0.008) and angiotensin II receptor type 2 C3123A polymorphism (P=0.032) in Iranian female participants. In conclusion, TT genotype of ACE A-240T seems to be a genetic risk factor for CAD in Iranian women.

Enduring Mystery of the Chromosome 9p21.3 Locus

Out of the long list of genetic loci that have been discovered by genome-wide association studies to be associated with a variety of clinical traits and diseases, one of the earliest such discoveries remains one of the most tantalizing. In 2007, 3 groups independently reported a locus on chromosome 9p21.3 to be associated with coronary artery disease (CAD), a finding that has been replicated by dozens of subsequent studies and seems to represent the single most important population-wide genetic risk factor for CAD. Especially noteworthy is that the locus has not been linked to any of the traditional CAD-risk factors, suggesting that the locus represents a novel pathogenetic mechanism that could potentially be exploited to develop an entirely new class of therapeutics. A study by Harismendy et al1 attempted to address this putative mechanism using a combination of genetic and epigenetic datasets to identify potential transcriptional regulatory elements in the locus, focusing on 1 element in which 2 linked index SNPs were predicted to create (non-CAD-risk alleles) versus disrupt (CAD-risk alleles) a canonical STAT1 transcription factor binding site. Experiments in cultured HeLa cells, human umbilical vein endothelial cells …

Genetic variants associated with myocardial infarction in the PSMA6 gene and Chr9p21 are also associated with ischaemic stroke

Ischaemic stroke shares common traditional risk factors with coronary artery disease (CAD) and myocardial infarction (MI). This study evaluated whether genetic risk factors for CAD and MI also affect susceptibility to ischaemic stroke in Caucasians and African Americans. Included in the study were a Caucasian series (713 ischaemic stroke patients, 708 controls) and a small African American series (166 ischaemic stroke patients, 117 controls). Twenty single-nucleotide polymorphisms (SNPs) previously shown to be associated with CAD or MI were genotyped and assessed for association with ischaemic stroke and ischaemic stroke subtypes using odds ratios (ORs) from multivariable logistic regression models. In Caucasians, four SNPs on chromosome 9p21 were significantly associated with risk of cardioembolic stroke, the strongest of which was rs1333040 (OR 1.55, P = 0.0007); similar but weaker trends were observed for small vessel stroke, with no associations observed regarding large vessel stroke. Chromosome 9p21 SNPs were also associated with risk of ischaemic stroke in African Americans (rs1333040, OR 0.65, P = 0.023; rs1333042, OR 0.55, P = 0.070; rs2383207, OR 0.55, P = 0.070). The PSMA6 SNP rs1048990 on chromosome 14q13 was associated with overall ischaemic stroke in both Caucasians (OR 0.80, P = 0.036) and African Americans (OR 0.31, P = 0.020). Our results provide evidence that chromosome 9p21 variants are associated with cardioembolic ischaemic stroke in Caucasians and with overall ischaemic stroke in African Americans. The PSMA6 variant rs1048990 also appears to affect susceptibility to ischaemic stroke in both populations. These findings require validation, particularly the preliminary findings regarding African Americans given the small size of that series.

The genetics of coronary artery disease

Prevention of coronary artery disease (CAD) is an appropriate goal for the 21st century. Randomized clinical studies consistently show a 30-40% reduction in mortality and morbidity by modifying known risk factors. However, genetic risk, estimated to account for 40-60% of susceptibility to CAD, has until recently been unknown. Comprehensive prevention will require knowledge of both. The 21st century technology has responded to the challenge. Whereas the first genetic risk variant was not discovered until 2007 (9p21), a total of 36 genetic risk factors for CAD have been discovered and verified in large sample sizes. A startling discovery was that over two-thirds of these factors do not act through known risk factors or mechanisms. This obviously has great implications for the pathogenesis of CAD and presents many potential targets for new therapy. These genetic risk factors occur more commonly in the population than expected, with over half of them occurring in more than 50% of the population, and 10 of them occurring in at least 75% of the population. The role of genetic risk factors in genetic screening for prevention of heart disease is yet to be defined. The technology is already available, but functional analysis may be a prerequisite for their clinical application.

Interaction between dyslipidaemia, oxidative stress and inflammatory response in patients with angiographically proven coronary artery disease

Coronary artery disease (CAD) is emerging as the biggest killer of the 21st century. A number of theories have been postulated to explain the aetiology of atherosclerosis. The present study attempts to elucidate the interaction, if any, between inflammation, oxidative stress and dyslipidaemia in CAD. A total of 753 patients undergoing angiography were evaluated and 476 were included in the study. The parameters studied included complete lipid profile, and apolipoprotein B, ferritin and nitric oxide (NO) levels. Statistical analysis was carried out to determine the interrelationship between these parameters and the best predictor of CAD risk. Cut-off points were determined from the receiver operating characteristics curves, and the specificity, sensitivity, positive predictive value, negative predictive value, odds ratio and confidence intervals were calculated. The levels of the parameters studied increased with the stenotic state and a positive correlation was observed between ferritin, NO and apolipoprotein B. NO emerged as the most reliable predictor of CAD, with an area under the curve of 0.992 and sensitivity and specificity of 97 and 98%, respectively. Environmental and genetic risk factors for CAD interact in a highly complex manner to initiate the atherosclerotic process. These risk factors should be considered mutually inclusive, not exclusive when devising pharmacological interventions, as multi-factorial risk management is the cornerstone of CAD management.

Creating a genetic risk score for coronary artery disease

Coronary artery disease (CAD) and its sequelae represent a significant health burden. Over the past two decades, numerous studies have attempted to link DNA sequence variation with the risk of CAD and related phenotypes. There has been significant evolution in technology from the early linkage studies within kindreds, and now we are able to use high-density genotyping to facilitate large-scale genome-wide association studies. The first novel genetic risk factor for CAD, 9p21.3, has been confirmed, and other loci are awaiting replication studies. The relative importance of each locus from a global standpoint and the incremental information conferred by testing for genetic variants remain to be determined.

Association of polymorphism in the thermolabile 5, 10-methylene tetrahydrofolate reductase gene and hyperhomocysteinemia with coronary artery disease

To determine the incidence of methylene tetrahydrofolate reductase (MTHFR) gene 677C-->T polymorphism and plasma homocysteine (Hcy) levels in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD) and to investigate the correlation between hyperhomocysteinemia (HHcy) and the presence of 677C-->T polymorphism. Elevated plasma Hcy level is an independent risk factor for CAD. A common mutation (677C-->T) in the gene coding for MTHFR has been reported to reduce the enzymatic activity and is associated with elevated levels of Hcy, especially in subjects with low folate intake. The study group comprised of 84 patients with CAD and 100 age-and-sex matched controls who had no history or clinical evidence of CAD and/or MI. DNA was extracted from peripheral blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hinf1, and gel electrophoresis. Conventional risk factors for CAD were prospectively documented. Allele and genotype frequencies in cases and control subjects were compatible with Hardy-Weinberg equilibrium. The frequencies of TT, CT, and CC genotypes among CAD patients were 4.8, 27.4, and 67.8% and in controls were 1.0, 19.0, and 80%. Hcy levels were higher in patients with triple-vessel disease compared to single and double vessel disease (P = 0.002). Multivariate analyses identified HHcy, diabetes mellitus, and hypertension as the independent predictors of CAD. HHcy appears to have a graded effect on the risk of CAD as well as the severity and extent of coronary atherosclerosis. Our findings support that homozygous genotype of MTHFR is a genetic risk factor for CAD. A further study with larger sample size including assessment of vitamin status is needed to better clarify the relationship between MTHFR genotypes and CAD.

Abstract 2319: Genetic Variations Of Mrf-2/Arid5b Confer Risk Of Coronary Artery Disease And Diabetes Mellitus In The Japanese Population

Mrf-2/Arid5b, a member of AT-rich interaction domain family of transcription factors, is highly expressed in the cardiovascular system and is believed to play essential roles in the phenotypic change through its regulation of smooth muscle cell differentiation. In addition, recent studies on gene-engineered mice suggested that this transcriptional factor is involved in obesity and adipogenesis, which are critical aspects of metabolic syndrome and diabetes mellitus. Thus, we hypothesized that genetic variations of the Mrf-2 gene may be associated with susceptibility to coronary artery disease (CAD) and diabetes mellitus (DM). To examine the association between Mrf-2 polymorphisms and CAD, we investigated 17 common SNPs of Mrf-2 in 475 CAD subjects and 310 control subjects. Four nearby SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) showed almost complete linkage disequilibrium, and disease associations were revealed not only for individual SNPs ( P =0.0002, rs2893880; P =0.0067, rs7087507, respectively) but also for their haplotype combination ( P =0.04, G-C-G-A (rs2893880-rs10740055-rs7087507-rs10761600)). Furthermore, these positive disease associations still existed after logistic regression analysis was performed to eliminate confounding conventional coronary risk factors. Subsequent analysis revealed that the aforementioned SNPs also statistically conferred risk of DM. To confirm these findings, we recruited another 500 DM subjects and 500 control subjects, and assessed the same haplotype block for their disease associations. Consistent significant associations were observed ( P =0.0238, rs2893880; P =0.0014, rs10740055; P =0.0067, rs7087507; P =0.0022, rs10761600; P =0.0031 and P =0.04, C-A-A-T and G-C-G-A (rs2893880-rs10740055-rs7087507- rs10761600), respectively). Moreover, the disease-associated genotypes were also revealed to be correlated with the level of serum adiponectin, which is known as an anti-diabetic adipocytokine. . In conclusion, our study implicates genetic variations of Mrf-2 as previously unknown genetic risk factors for CAD and DM. We believe that the associations of Mrf-2 with CAD may be mediated at least partly via its associations with DM.