Variants For Coronary Artery Disease Research Articles

Genome-wide association study of coronary artery disease in the Japanese

A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10(-34)), HLA-DQB1 on 6p21 (P=4.7 × 10(-7)), and CDKN2A/B on 9p21 (P=6.1 × 10(-16)). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10(-40)). On 6p21, an HLA allele, DQB1(*)0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects - population specific and common - on susceptibility to CAD.

Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour.

Coronary artery disease (CAD) is the leading cause of death worldwide. Affected individuals cluster in families in patterns that reflect the sharing of numerous susceptibility genes. Genome-wide and large-scale gene-centric genotyping studies that involve tens of thousands of cases and controls have now mapped common disease variants to 34 distinct loci. Some coronary disease common variants show allelic heterogeneity or copy number variation. Some of the loci include candidate genes that imply conventional or emerging risk factor-mediated mechanisms of disease pathogenesis. Quantitative trait loci associations with risk factors have been informative in Mendelian randomization studies as well as fine-mapping of causative variants. But, for most loci, plausible mechanistic links are uncertain or obscure at present but provide potentially novel directions for research into this disease's pathogenesis. The common variants explain ∼4% of inter-individual variation in disease risk and no more than 13% of the total heritability of coronary disease. Although many CAD genes are presently undiscovered, it is likely that larger collaborative genome-wide association studies will map further common/low-penetrance variants and hoped that low-frequency or rare high-penetrance variants will also be identified in medical resequencing experiments.

The role of PRKCH gene variants in coronary artery disease in a Chinese population

The aim of the present study was to assess the influences of PRKCH gene variants (1425G/A and _15) on the risk of coronary artery disease (CAD) in a Chinese population. Our study population consisted of 470 CAD patients and 434 control subjects. The alleles frequencies of the two variants were significantly higher among CAD patients than control subjects (P = 0.001 for 1425G/A and P = 0.001 for _15, respectively). In the CAD group, the A allele carriers of 1425G/A and _15 polymorphisms had higher low-density lipoprotein cholesterol (LDL-C) levels than homozygote G allele carriers (P = 0.001 and P = 0.021, respectively). In a multiple logistic regression model adjusted for age, sex, body mass index (BMI), etc., a markedly increased risk of developing CAD was found in subjects carrying GA or AA genotype (P = 0.005 and P = 0.018, respectively). In conclusion, we observed that there was a remarkable association of minor alleles (1425G/A and _15) in the PRKCH gene with an elevated risk of CAD and increased levels of LDL-C in this Chinese population.

Heart rate variability and heart rate recovery in patients with coronary artery ectasia

Coronary artery ectasia (CAE) is characterized by an abnormal dilatation of the coronary arteries, which is a variant of coronary artery disease (CAD). Increased sympathetic activity or decreased vagal modulation of cardiac function assessed by heart rate variability (HRV) analysis has been associated with an increased risk of coronary artery disease and mortality and angiographic progression of coronary atherosclerosis, as well as arrhythmia and sudden cardiac death. Heart rate recovery index is a strong indicator of risk in asymptomatic and symptomatic CAD. To the best of our knowledge, no study has been conducted to investigate the relationship between HRV, heart rate recovery, and CAE. The purpose of this study was to examine the changes in heart rate recovery and HRV measurements in coronary artery ectasia. The study population consisted of 50 consecutive patients (24 women; mean age 46+/-5 years) with CAE, and 35 asymptomatic healthy individuals comprised the control group (19 women; mean age 44+/-7 years). We performed electrocardiography, echocardiography, Holter analysis, exercise stress test, routine biochemical tests and evaluated the clinical characteristics. Time-domain parameters of HRV (mean R-R intervals; standard deviations of all N-N intervals; standard deviations of the averages of N-N intervals), the root mean square of the difference in successive R-R intervals, proportion derived by dividing the number of interval differences of successive N-N intervals greater than 50 ms by the total number of N-N intervals (pNN50) were evaluated. Heart rate recovery was defined as the difference in the heart rate from peak exercise to 1 min after peak exercise. Standard deviations of all N-N intervals (123.7+/-30.3 vs. 178.8+/-52.7, P<0.001), standard deviations of the averages of N-N intervals (95.2+/-27.1 vs. 120.2+/-39.6, P = 0.001), total number of N-N intervals (11.9+/-8.6 vs. 17.1+/-6.4, P = 0.004) were significantly lower in the CAE group than in healthy controls. The root mean square of the difference in successive R-R intervals was lower in CAE patients than controls, but the differences between groups were not statistically significant (47.5+/-23.1 vs. 56.2+/-23.6, P = 0.097). The heart rate recovery values measured during the recovery phase were significantly lower in the CAE group compared with the control group (21.3+/-11.1 vs. 29.3+/-11.9, P = 0.002). The incidence of abnormal heart rate recovery [22 (44%) vs. 5 (14%), P = 0.002] was greater in patients with CAE group than in controls. The results of this study showed that time-domain HRV parameters and heart rate recovery were reduced in patients with CAE.

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

Coronary artery disease (CAD) is caused by a thrombotic occlusion or spasm of the coronary artery. Association of genetic variants with susceptibility to CAD has been reported in various populations, but the association should be replicated in other populations to establish the role of genetic variants in CAD. We conducted a case-control study with a total of 1480 CAD cases and 2115 controls from two East Asian populations, Japanese and Korean, to validate the associations of CAD with eight single nucleotide polymorphisms (SNPs) in eight loci, which were identified from large-scale whole-genome association studies in Europeans or East Asians. Among the tested SNPs, one SNP in BRAP (rs11066001) showed a significant association in allele frequency distribution with CAD in both the Japanese (Odds ratio (OR)=1.63, 95% confidence interval (CI); 1.41-1.89, P=5.0 x 10(-11), corrected P (Pc)=4.0 x 10(-10)) and Korean populations (OR=1.68, 95% CI; 1.41-2.00, P=6.5 x 10(-9), Pc=5.2 x 10(-9)), and a meta-analysis showed a significant association in the East Asian populations (OR=1.65, 95% CI; 1.48-1.85, P=1.8 x 10(-18), Pc=1.4 x 10(-17)), whereas no evidence of association was found for the other SNPs. In addition, a combined analysis of BRAP and another CAD locus on 9p21 suggested that these loci had a synergistic role in the susceptibility. Failure to replicate the association with the other SNPs, which were reported in the European populations, suggested that their contributions to CAD were not large enough to be readily captured in the East Asian populations.

Comparison of serum levels of inflammatory markers and allelic variant of interleukin-6 in patients with acute coronary syndrome and stable angina pectoris

Although the relationship between atherosclerosis and inflammatory cells has been recognized in recent years, the effect of interleukin-6 (IL-6) genetic variants associated with atherosclerosis is still controversial. Therefore, we investigated the association between IL-6 polymorphism and levels of IL-6 in patients with coronary artery disease (CAD). We conducted a case-control study on 294 unrelated participants who were referred to the cardiology department of the university hospital for coronary angiography because of suspected ischemic heart disease. Group I comprised patients with clinically acute coronary syndrome, and group II comprised patients (individuals matched for age and sex) with clinically stable angina pectoris; both groups were categorized, based on their angiographic findings, as either having angiographically documented less extensive CAD (1 vessel narrowed) or extensive CAD (> or =2 vessels narrowed). They were studied to examine effect of the IL-6 gene variants in CAD. Genotyping was determined by polymerase chain reaction. The IL-6 G/C-174 polymorphism was found in 19 of 106 (18%) in group I and in four of 188 (2%) in group II (P<0.001). Median IL-6 levels were significantly higher in group I (6.7+/-13.6 pg/ml) than in group II (4.1+/-3.8 pg/ml) (P<0.05). In addition, high sensitivity C-reactive protein levels were significantly higher in group I (8.2+/-6.2 mg/dl) than in group II (4.6+/-3.4 mg/dl) (P<0.001). These results demonstrated that the presence of the IL-6 G/C-174 polymorphism and increased IL-6 and high sensitivity C-reactive protein levels are strongly associated with the inflammatory system and the course of clinical and hemodynamically significant CAD.

Increased platelet activity in patients with isolated coronary artery ectasia

The common coexistence with coronary artery disease has led to the suggestion that coronary artery ectasia (CAE) is a variant of coronary artery disease. The mechanisms, however, responsible for CAE formation during the atherosclerotic process and the exact clinical significance are not well known. In this study, we aimed to investigate platelet activity in patients with isolated CAE by using specific markers of platelet activation as P-selectin, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4). Thirty-two patients with isolated CAE without significant stenosis and 30 control participants with angiographically normal coronary arteries were included in this study. According to the angiographic definition used in the Coronary Artery Surgery Study, a vessel is considered to be ectasic when its diameter is > or = 1.5 times that of the adjacent normal segment in segmental ectasia. Plasma P-selectin, beta-TG and PF4 levels were measured in all patients and control participants using enzyme-linked immunosorbent assay method. Patients with isolated CAE were detected to have significantly higher levels of plasma P-selectin, beta-TG and PF4 in comparison with control participants with angiographically normal coronary arteries (P-selectin: 248+/-46 vs. 154+/-32 ng/ml, respectively, P<0.001; beta-TG: 51+/-19 vs. 21+/-9 ng/ml, respectively, P<0.001; PF4: 58+/-23 vs. 33+/-11 ng/ml, respectively, P<0.001). In conclusion, we have shown for the first time that patients with isolated CAE have raised levels of plasma P-selectin, beta-TG and PF4 compared with control participants with angiographically normal coronary arteries, suggesting increased platelet activation in patients with CAE.