Association of CDKN2BAS polymorphism rs4977574 with coronary heart disease: a case-control study and a meta-analysis.
ABSTRACT: The goal of our study was to explore the significant association between a non-protein coding single nucleotide polymorphism (SNP) rs4977574 of CDKN2BAS gene and coronary heart disease (CHD). A total of 590 CHD cases and 482 non-CHD controls were involved in the present association study. A strong association of rs4977574 with CHD was observed in females (genotype: p=0.002; allele: p=0.002, odd ratio (OR)=1.57, 95% confidential interval (CI)=1.18-2.08). Moreover, rs4977574 was more likely to be a risk variant of CHD under the recessive model in females (?2=10.29, p=0.003, OR=2.14, 95% CI=1.31-2.77). A breakdown analysis by age had shown that there was an 87% increased risk of CHD for females younger than 65 years (genotype: ?2=14.64, degrees of freedom (df)=2, p=0.0002; allele: ?2=11.31, df=1, p=0.0008, OR=1.87, 95% CI=1.30-2.70). Similar observation was also found in males younger than 65 years (genotype: ?2=8.63, df=2, p=0.04; allele: ?2=7.55, df=1, p=0.006, OR=1.45, 95% CI=1.11-1.90). p values were adjusted by age, sex, smoking, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Meta-analysis of 23 studies among 36,452 cases and 39,781 controls showed a strong association between rs4977574 and the risk of CHD (p<0.0001, OR=1.27, 95% CI=1.22-1.31).
Project description:Westaway et al. have revealed a significant association between common variants of calsequestrin-2 (CASQ2) and nitric oxide synthase 1 (neuronal) adaptor protein (NOS1AP) and the risk of sudden death in patients of coronary heart disease (CHD). In light of the findings, we aim to explore the association between variants of the two genes and CHD risk in Han Chinese. Our results show a significant contribution of rs10918859 of the NOS1AP gene to CHD in Han Chinese (genotype: ?(2)=8.33, df=2, p=0.015; allele: ?(2)=4.00, df=1, p=0.047, odds ratio [OR]=1.44, 95% confidence interval [CI]=1.00-2.05). The association of rs10918859 with CHD is seen only in men (genotype: ?(2)=7.81, df=2, p=0.02; allele: ?(2)=4.49, df=1, p=0.03, OR=1.66, 95% CI=1.03-2.66). Moreover, rs10918859 is likely to exert its effect under a dominant model in men (?(2)=7.6, df=1, p=0.005, OR=2.46, 95% CI=1.29-4.71). No association is observed between CASQ2 variants and CHD risk. The frequencies of rs12084280-C and rs10918859-A are higher in Han Chinese (36.7% and 41.6%) than those in Europeans (11% and 19.4%, respectively). These ethnic differences imply that further validation of NOS1AP in the susceptibility of CHD in other populations is warranted. We confirm that rs10918859 of the NOS1AP gene is associated with CHD in Han Chinese. In addition, here we report a gender effect in the association between rs10918859 of the NOS1AP gene and CHD.
Project description:OBJECTIVE:Blood lipids are well-known risk factors for coronary heart disease (CHD). The aim of this study was to explore the association between 17 lipid-related gene polymorphisms and CHD. METHODS:The current study examined with 784 CHD cases and 739 non-CHD controls. Genotyping was performed on the MassARRAY iPLEX® assay platform. RESULTS:Our analyses revealed a significant association of APOE rs7259620 with CHD (genotype: ?2=6.353, df=2, p=0.042; allele: ?2=5.05, df=1, p=0.025; recessive model: ?2=5.57, df=1, p=0.018). A further gender-based subgroup analysis revealed significant associations of APOE rs7259620 and PPAP2B rs72664392 with CHD in males (genotype: ?2=8.379, df=2, p=0.015; allele: ?2=5.190, df=1, p=0.023; recessive model: ?2=19.3, df=1, p<0.0001) and females (genotype: ?2=9.878, df=2, p=0.007), respectively. Subsequent breakdown analysis by age showed that CETP rs4783961, MLXIPL rs35493868, and PON2 rs12704796 were significantly associated with CHD among individuals younger than 55 years of age (CETP rs4783961: ?2=8.966, df=1, p=0.011 by genotype; MLXIPL rs35493868: ?2=4.87, df=1, p=0.027 by allele; ?2=4.88, df=1, p=0.027 by dominant model; PON2 rs12704796: ?2=6.511, df=2, p=0.039 by genotype; ?2=6.210, df=1, p=0.013 by allele; ?2=5.03, df=1, p=0.025 by dominant model). Significant allelic association was observed between LEPR rs656451 and CHD among individuals older than 65 years of age (?2=4.410, df=1, p=0.036). CONCLUSION:Our study revealed significant associations of APOE, PPAP2B, CETP, MLXIPL, PON2, and LEPR gene polymorphisms with CHD among the Han Chinese.
Project description:BACKGROUND:Rs4977574 (A?>?G) and Rs1333045 (C?>?T) are both single nucleotide polymorphisms (SNPs) related with coronary artery disease, locating on chromosome 9p21.3. The study aimed to identify the correlation between rs4977574 and rs1333045 polymorphism genotypes and coronary heart disease (CHD) in a Chinese population. METHODS:Blood samples were collected from 855 subjects. A case-control study was used in this experiment, and 598 cases in the CHD group and 257 subjects in the control group were enrolled. Genotyping was identified by the Agena MassARRAY system. Statistical analysis was conducted by SPSS (Ver 16.0) and plink (Ver. 1.07, Shaun Purcell). Haplotype analysis was performed using Haploview software. RESULTS:Association analysis by plink indicated a significant difference in the allele distribution for single nucleotide polymorphisms between cases and controls (rs4977574 P?=?0.003, rs1333045 P?=?0.035). Fisher's exact test by plink proved that allele G may be associated with a higher risk of CHD (P?=?0.003, odds ratio (OR) =?1.371) and the T allele was likely to reduce the risk of coronary events (P?=?0.035, OR?=?0.798). The serum levels of apolipoprotein A (ApoA) were higher in subjects with the AG?+?AA genotype of rs4977574 compared to those with the GG genotype (P?=?0.028). In the dominant model of rs1333045, the levels of ApoA were higher and LDL levels were lower in the TC?+?TT genotype than in the CC genotype. CONCLUSIONS:The present study examined the association between the 9p21 chromosome rs4977574 and rs1333045 polymorphism genotypes and CHD in a population of Chinese patients. The G allele of rs4977574 and the C allele of rs1333045 are the susceptibility sites of CHD.
Project description:<h4>Objective</h4>Apolipoprotein A5 (APOA5) is associated with plasma triglyceride (TG) levels, a risk factor for coronary heart disease (CHD). This study explored the association between CHD and the APOA5 rs662799 polymorphism.<h4>Methods</h4>We collected 1,521 samples (783 CHD patients and 738 controls) for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software.<h4>Results</h4>Significant differences were observed between CHD cases and controls at the level of both genotype (?2 = 8.964, df = 2, P = 0.011) and allele (?2 = 9.180, df = 1, P = 0.002, OR = 1.275, 95% CI = 1.089-1.492). A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males (?2 = 7.770, df = 1, P = 0.005; OR = 1.331, 95% CI = 1.088-1.628). An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001).<h4>Conclusion</h4>Both our case-control study and meta-analysis confirm a significant association between APOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD.
Project description:OBJECTIVE:Coronary heart disease (CHD) is the most common cause of death worldwide. This study aimed to validate the association of the rs964184 polymorphism with the CHD risk and included 874 CHD patients and 776 controls. METHODS:rs964184 polymorphism genotyping was performed using Tm-shift polymerase chain reaction. RESULTS:A strong association of the rs964184 polymorphism with CHD was found (genotype: X2=14.365, p=0.001; allele: X2=14.191, p=1.67x10-4; power=0.965). Gender analysis revealed a significant association only in males (genotype: X2=12.387, p=0.002; allele: X2=12.404, p=4.32x10-4; OR=1.467, 95% CI=1.185-1.817, power=0.945). Age and gender analyses revealed significant associations of the rs964184 polymorphism with CHD in males between the ages of 55 and 65 years (genotype: X2=10.070, p=0.007; allele: X2=10.077, p=0.002; OR=1.706, 95% CI=1.224-2.377, power=0.996) and in females older than 65 years (genotype: X2=9.462, p=0.009; allele: X2=9.560, p=0.002; OR=2.112, 95% CI=1.308-3.412, power=0.994). Further subgroup analysis suggested that rs964184 genotypes were significantly associated with TG levels in the patients (r=0.191, adjusted p=1.05x10-5) and controls (r=0.101, adjusted p=0.026). CONCLUSION:Our results indicate that both gender and age have great impacts on the association of the rs964184 polymorphism with CHD among Chinese.
Project description:The single nucleotide polymorphisms (SNPs) related to both coronary heart disease (CHD) and ischemic stroke (IS) in Chinese individuals have not been identified definitely. This study was developed to evaluate the genetic susceptibility to CHD and IS on the chromosome 9p21 and the adenosine triphosphate (ATP)-binding cassette transporter A1 genes (ABCA1) in a Chinese Han population. Genotypes of the rs1333040, rs1333042, rs4977574, rs2066715 and rs2740483 SNPs were determined in 1134 unrelated patients (CHD, 565 and IS, 569) and 541 controls. The frequencies of the rs4977574 genotypes and alleles between CHD and control groups, and the rs2740483 genotypes and alleles between IS and control groups were different (p = 0.006-0.001). The subjects with rs1333042GG genotype and the carriers of the rs4977574G allele were associated with increased risk of CHD. The carriers of the rs4977574G allele were associated with increased risk of IS. However, the carriers of the rs2740483C allele had lower risk of IS than the non-carriers of the rs2740483C allele after controlling for potential confounders. The rs4977574GG-age (>60 year) interaction increased the risk of CHD (p = 0.022), whereas the rs2740483CG/CC-body mass index (>24 kg/m²) interaction decreased the risk of IS (p = 0.035). The interactions of rs1333040-rs1333042 on the risk of CHD and IS were relatively strong, whereas the interactions of rs1333040-rs1333042-rs2066715 and rs1333040-rs1333042-rs2066715-rs2740483 on the risk of CHD, and rs1333040-rs1333042-rs4977574 and rs1333040-rs1333042-rs4977574-rs2740483 on the risk of IS were relatively weak. These findings suggest that some common variants on the chromosome 9p21 and ABCA1 and their interactions may significantly modify the risk of CHD and IS independent of effects on serum lipid levels.
Project description:The objective of the present study was to explore the association between intercellular adhesion molecule 1 (ICAM1) polymorphisms (rs5498 and rs3093030) and diabetic foot (DF) susceptibility in a Chinese Han population.128 type 2 diabetes mellitus (T2DM) patients with DF, 147 T2DM patients without DF, and 155 healthy individuals were enrolled in this study. ICAM1 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotypes and alleles of the polymorphisms were compared by ? test between the 2 groups. Association between ICAM1 polymorphisms and DF susceptibility was expressed through odds ratio (OR) with corresponding 95% confidence interval (95%CI). Effects of ICAM1 polymorphisms on DF clinical characteristics were analyzed by t test.GG genotype of rs5498 polymorphism was distinctly correlated with decreased T2DM risk (OR?=?0.369, 95%CI?=?0.152-0.895) and reduced susceptibility to DF among healthy controls (OR?=?0.316, 95%CI?=?0.119-0.837). Similar results were discovered between rs5498 G allele and decreased risk of T2DM (OR?=?0.676, 95%CI?=?0.475-0.963) and DF (OR?=?0.656, 95%CI?=?0.453-0.950) among healthy controls. Individuals carrying rs3093030 T allele had low susceptibility to DF developed from T2DM (OR?=?0.634, 95%CI?=?0.412-0.974). DF patients carrying rs5498 AA genotype had significantly higher serum creatinine levels than GG genotype carriers (P?=?.003).ICAM1 rs3093030 polymorphism may act as a protective factor against DF developed from T2DM, moreover, rs5498 may be involved in onset of T2DM.Clinical trial number: ChiCTR-INR-18010231.
Project description:It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N = 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95%CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I(2) = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I(2)<7.5%, p>0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80).We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.
Project description: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?<?.05). CONCLUSION:The ANRIL polymorphism rs4977574 is associated with CAD risk in Asian population. The rs4977574 with G allele may confer to a higher risk of CAD, especially MI.
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.