ANRIL polymorphism rs4977574 is associated with increased risk of coronary artery disease in Asian populations: A meta-analysis of 12,005 subjects.
ABSTRACT: BACKGROUND:Several studies have shown that ANRIL polymorphism may be associated with the risk of coronary artery disease (CAD). However, these studies do not provide a clear consensus in Asian population. Thus, this meta-analysis was aimed to evaluate the relationship between the common variant rs4977574 in ANRIL and CAD risk in Asian population. METHODS:We conducted a systematic literature search of PubMed, Embase and the Cochrane Library and 2 Chinese databases. A total of 12,005 subjects from 6 independent studies were included. The pooled odds ratio (OR) and their corresponding 95% confidence intervals (CIs) were used to assess the association between rs4977574 and CAD using random effects model. RESULTS:A significant association was observed between rs4977574 and CAD risk under the allelic (OR: 1.18, 95% CI: 1.04-1.34, P?=?.010), recessive (OR: 1.27, 95% CI: 1.01-1.60, P?=?.04), dominant (OR: 1.28, 95% CI: 1.13-1.44, P?=?.002), homozygous (OR: 1.46, 95% CI: 1.15-1.86, P?=?.002), and heterozygous model (OR: 1.17, 95% CI: 1.07-1.28, P?=?.0004), especially in the Chinese subgroup and the myocardial infarction (MI) subgroup (P?
Project description:BACKGROUND:The long noncoding RNAs have gradually been reported to be an important class of RNAs with pivotal roles in the development and progression of myocardial infarction (MI). In this study, we hypothesized that genetic variant of cyclin-dependent kinase inhibitor 2B antisense RNA (ANRIL) may affect the prognosis of MI patients. METHODS:A systematic review and meta-analysis of studies including 11,269 cases and 10,707 controls on the association of 5 ANRIL single nucleotide polymorphism and the overall risk of MI or coronary artery disease (CAD) was performed. RESULTS:In the meta-analysis, rs4977574 A?>?G, rs1333040?C?>?T, rs1333042 A?>?G and rs10757274 A?>?G ANRIL polymorphisms were correlated with overall MI or CAD risk. No significant associations were found between ANRIL rs1333049 G?>?C polymorphism and CAD risk. CONCLUSIONS:The results indicated that ANRIL polymorphism (rs4977574, rs1333040, rs1333042, and rs10757274) were more generally associated with CAD or MI risk. Further experimental studies to evaluate the limits of this hypothesis are warranted, and future functional studies are required to clarify the possible mechanisms.
Project description:BACKGROUND: Recent genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). The associations of those SNPs with myocardial infarction (MI) have not been replicated in Asian populations. Among those previously identified SNPs, we selected nine (rs10953541, rs1122608, rs12190287, rs12413409, rs1412444, rs1746048, rs3798220, rs4977574, rs579459, in or near genes 7q22, LDLR, TCF21, CYP17A1, LIPA, CXCL12, LPA, CDKN2A, ABO, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population. METHODS AND RESULTS: We conducted a case-control association study on a cohort of 2365 MI patients and 2678 unrelated controls from the Chinese population. Genotyping of 9 SNPs were performed by the TaqMan Real Time PCR method. After age, sex, and BMI adjustment, we observed the SNPs rs12190287, rs12413409, rs1412444, rs1746048 and rs4977574, were significantly associated with MI in additive models and rs12190287, rs12413409, rs4977574 were significantly associated with phenotypes of MI at the same time. We also found three SNPs rs1122608, rs3798220 and rs579459 were significantly associated with risk factors of MI, although they had no association with MI in Chinese population. CONCLUSION: Results of this study indicate that 5 SNPs were associated with MI and 3 SNPs were associated with associated with lipoprotein levels but not with MI in a Chinese population. The present study supports some CAD-related genes in Caucasian as important genes for MI in a Chinese population.
Project description:AIMS: Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors. METHODS AND RESULTS: A total of 24,944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N?=?2309), ischemic stroke (N?=?1253) and CVD-mortality (N?=?1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P?=?0.035) and CVD-mortality (P?=?0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N?=?9642) for CAD (HR?=?1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR?=?1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N?=?7000) for both CAD (HR?=?1.05; 95%CI 0.95-1.16; P?=?0.326) and CVD-mortality (HR?=?1.08; 95%CI 0.94-1.23; P?=?0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574. CONCLUSION: Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.
Project description:Chromosome 9p21 variants are among the most robust genetic markers for coronary artery disease (CAD), and previous studies have suggested that genetic effects of this locus might be modified by dietary factors. Intake of sugar-sweetened beverages (SSBs), which are the main dietary source of added sugar, has been shown to interact with genetic factors in affecting CAD risk factors such as obesity.We aimed to test whether SSB intake modified the association between chromosome 9p21 variants and CAD risk in Hispanics living in Costa Rica.The current study included 1560 incident cases of nonfatal myocardial infarction (MI) and 1751 population-based controls. Three independent single nucleotide polymorphisms (SNPs) at the chromosome 9p21 locus were genotyped. SSB intake was assessed with the use of a food-frequency questionnaire and was defined as the frequency of intake of daily servings of sweetened beverages and fruit juice.We showed a significant interaction between SSB intake and one of the 3 variants (i.e., rs4977574) on MI risk. The per–risk allele OR (95% CI) of rs4977574 for MI was 1.44 (1.19, 1.74) in participants with higher SSB consumption (>2 servings/d), 1.21 (1.00, 1.47) in those with average consumption (1–2 servings/d), and 0.97 (0.81, 1.16) in subjects with lower consumption (<1 serving/d; P-interaction = 0.005). A genetic risk score derived from the sum of risk alleles of the 3 SNPs also showed a significant interaction with SSB intake on MI risk (P-interaction = 0.03).Our data suggest that unhealthy dietary habits such as higher intake of SSBs could exacerbate the effects of chromosome 9p21 variants on CAD.
Project description:ANRIL (antisense non-coding RNA in the INK4 locus), located at the 9p21.3 locus, has been known to be closely associated with the risk of coronary artery disease (CAD). To date, studies of the 9p21.3 variants on CAD risk mainly focus on the non-coding region of ANRIL. However, the biological significance of the variants on ANRIL promoter and exons is still unknown. Here we investigate whether the variants on ANRIL promoter and exons have an effect on myocardial infarction (MI) risk, and further analyze the association of these variants with the expression of ANRIL transcript. We did not find any common variants with minor allele frequencies (MAF) larger than 5% in ANRIL promoter by sequencing 1.6kb upstream of the start codon. Unconditional logistic regression analysis revealed that two SNPs in ANRIL exons, rs10965215 and rs10738605, were significantly associated with MI risk. Further studies revealed that ANRIL transcript EU741058.1 expression levels of rs10965215 and rs10738605 risk genotypes were borderline lower than those of protective genotypes. Our data provide the evidence that the variants rs10965215 and rs10738605 in ANRIL exons contribute to MI risk in the Chinese Han population which might be correlated with the expression of its transcript EU741058.1.
Project description:Myocardial infarction (MI) patients without obstructive coronary artery disease (CAD) are at increased risk for recurrent ischemic events, but angina frequency post-MI has not been described.Among MI patients who underwent angiography, we assessed angina at baseline, 1, 6, and 12 months using the Seattle Angina Questionnaire (SAQ). A hierarchical repeated measures modified Poisson model assessed the association between the absence of obstructive CAD (defined as epicardial stenoses >70% or left main >50%) and angina. Among 5539 MI patients from 31 US hospitals (mean age 60, 68% male), 6.9% had no angiographic obstructive CAD. More patients without obstructive CAD (vs. obstructive CAD) were female (57% vs 30%), non-white (51% vs 24%) and had NSTEMI (87% vs 51%). In unadjusted analyses, patients without obstructive CAD had less angina prior to MI but more angina and worse health status post-discharge. After adjustment for socio-demographic and clinical factors, the risk of post-MI angina was similar in patients without vs. with obstructive CAD (IRR=0.89, 95% CI 0.77-1.02). Among patients without obstructive CAD, depression and self-reported avoidance of care due to cost were independently associated with angina (IRR=1.28 per 5 points on PHQ, 95% CI 1.17-1.41; IRR=1.34, 95% 1.02-1.1.74).Following MI, patients without obstructive CAD experience an angina burden at least as high as those with obstructive CAD, affecting 1 in 4 patients at 12 months. As these patients are not candidates for revascularization, other anti-anginal strategies are needed to improve their health status and quality of life.
Project description:Many studies conducted worldwide substantiate a role of genetic polymorphisms in non-coding regions linked with coronary artery disease (CAD). One such single nucleotide polymorphism (SNP) of a non-coding RNA in the INK4 locus (ANRIL) i.e. rs1333049 C/G in the vicinity of cell cycle regulating genes is documented to have a role in CAD risk. In this study we aimed to determine the association of ANRIL rs1333049 C/G with CAD in a North Indian population. Five hundred disease free controls and 500 CAD patients were genotyped using allele specific ARMS-PCR method. High risk association of rs1333049 was seen in both heterozygous and mutant genotypes (OR=2.883, 95% CI=1.475-5.638 and p=0.002 and OR=6.717, 95% CI=3.444-13.102 and p < 0.001 respectively). Gender stratified analysis revealed risk association in both heterozygous and mutant genotypes in males. However, risk association in the mutant genotype and females was documented. Similarly, risk association was seen in subjects above 40 years of age in heterozygous and mutant genotypes. Similarly, risk association was reported in obese, sedentary lifestyle, positive family history and smoking in the heterozygous and mutant genotype and with diabetes in the mutant GG genotype. The study revealed high risk association of ANRIL rs1333049 with CAD and other risk factors.
Project description:OBJECTIVE:Recent genome-wide association studies have established that polymorphisms within CDKN2B-AS1 of chr9p21.3 locus increased susceptibility to coronary artery disease (CAD) or myocardial infarction. Common variants of CDKN2B-AS1 (including rs4977574 A>G and rs1333040 C>T) are determined to be directly associated with CADs in many populations worldwide and suggested biomarkers for the early detection of CAD. There is a lack of investigation for the association between CDKN2B-AS1 rs4977574 A>G and rs1333040 C>T genetic modifiers and CAD in a Turkish Cypriot population. The aim of the present study was to investigate the potential effects of these variants on susceptibility to developing CAD in a Turkish Cypriot population and their contribution to lipid metabolism. METHODS:Seventy-one patients with angiography-confirmed CAD were recruited to the CAD group, whereas 153 voluntary subjects without CAD symptoms were enrolled to the control group. Genotyping for the CDKN2B-AS1 gene polymorphisms was performed by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. RESULTS:There is no statistical significant association observed between rs4977574 and rs1333040 single-nucleotide polymorphisms and two studied groups [odds ratio (OR): 0.763, p=0.185, 95% confidence interval (CI): 0.511-1.139 and OR: 1.060, p=0.802, 95% CI: 0.672-1.671, respectively]. However, rs2977574 G and rs1333040 T alleles-the risk alleles-were found to be associated with higher level of serum total cholesterol and lower level of high-density lipoprotein-cholesterol in the CAD group (p=0.019, p=0.006 and p=0.022, p=0.031, respectively). To our knowledge, this is the first study that establishes the effect of rs1333040 on lipid metabolism. CONCLUSION:The presence of rs4977574 G and rs1333040 T alleles and interaction may exist as environmental factors associated with lipid metabolism and might be responsible for the development of CAD in a Turkish Cypriot population.
Project description:Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases?=?270/Ncontrols?=?5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication?=?2.19?×?10-12, OR?=?1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P?<?5?×?10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P?=?0.021, OR?=?1.82?[95%?CI:?1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P?=?1.28?×?10-17, HR?=?0.91?[95%?CI?:0.89-0.93], for MI) and Million Veteran Program (P?=?9.33?×?10-36, OR?=?0.95?[95%?CI:?0.94-0.96], for CAD; P?=?3.35?×?10-6, OR?=?0.96?[95%?CI:?0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.
Project description:BACKGROUND:The aim of the current study was to evaluate the association of PAI-1 4G/5G polymorphism with coronary artery disease (CAD) risk using a meta-analysis. METHODS:All eligible studies were identified through a search of PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Database of Chinese Scientific and Technical Periodicals, and China Biology Medical literature database (CBM) before June 2014. The association between the PAI-1 4G/5G polymorphism and CAD risk was estimated by odds ratio (OR) and 95% confidence interval (CI). RESULTS:A total of 72 studies including 23557 cases and 21526 controls were eventually collected. The PAI-1 4G/5G polymorphism was significant associated with CAD risk in overall population (OR=1.19, 95% CI 1.10-1.28, P < 0.00001). The combination of adjusted ORs for CAD was 1.20 (95% CI 1.03-1.40, P=0.02). This polymorphism was associated with CAD risk in Caucasians (OR=1.10, 95% CI 1.02-1.19, P=0.01) and Asians (OR=1.46, 95% CI 1.21-1.75, P < 0.0001). This polymorphism significantly increased MI risk (OR=1.15, 95% CI 1.06-1.25, P=0.001). In the subgroup analysis by age, this polymorphism was significantly associated with early-onset CAD risk (OR=1.21, 95% CI 1.02-1.43, P=0.03). In the gender subgroup analyses, a statistically significant association was found in male CAD patients (OR=1.10, 95% CI 1.01-1.20, P=0.04). Both T2DM patients and non-T2DM patients carrying 4G allele showed increased CAD risks (OR=2.23, 95% CI 1.27-3.92, P=0.005 and OR=1.64, 95% CI 1.19-2.25, P=0.002, respectively). CONCLUSIONS:This meta-analysis suggested that PAI-1 4G/5G polymorphism was a risk factor for CAD.