Susceptibility To Dilated Cardiomyopathy Research Articles

Association between MMP2 gene polymorphisms and dilated cardiomyopathy in a Chinese Han population.

Dilated cardiomyopathy (DCM) belongs to the common types of cardiomyopathies. The pathogenesis remains unclear despite the fact that various genes have been found associated with DCM. MMP2 is a zinc-dependent and calcium-containing secreted endoproteinases, which could cleave a broad spectrum of substrates including extracellular matrix components and cytokines. It has proved to play an important role in the cardiovascular diseases. This study aimed to investigate the potential role of MMP2 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population. A total of 600 idiopathic DCM patients and 700 healthy controls were enrolled. Patients with contact information were followed up for a median period of 28months. Three tagged single nucleotide polymorphisms (rs243865, rs2285052, and rs2285053) in the promoter of MMP2 gene were genotyped. A series of function analysis were conducted to illuminate the underlying mechanism. The frequency of rs243865-C allele was increased in DCM patients when compared with healthy controls (P=0.001). Genotypic frequencies of rs243865 were associated with the susceptibility of DCM in the codominant, dominant, and overdominant models (P<0.05). Besides, rs243865-C allele presented a correlation with the poor prognosis of DCM patients in both dominant (HR=2.0, 95% confidence interval [CI]=1.14-3.57, P=0.017) and additive (HR=1.85, 95% CI=1.09-3.13, P=0.02) model. The statistical significance remained after adjustment for sex, age, hypertension, diabetes, hyperlipidaemia, and smoking status. There were significant differences in left ventricular end-diastolic diameter and left ventricular ejection fraction between rs243865-CC and CT genotypes. Functional analysis indicated that rs243865-C allele increased luciferase activity and the mRNA expression level of MMP2 by facilitating ZNF354C binding. Our study suggested that MMP2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese Han population.

Analysis of SIRT4 gene single-nucleotide polymorphisms in a Han Chinese population with dilated cardiomyopathy.

Aim: We aimed to investigate the association of SIRT4 gene polymorphisms with the susceptibility and prognosis of dilated cardiomyopathy (DCM) in a Chinese population. Materials & methods: A total of 369 controls and 373 DCM patients were enrolled. Three tag single-nucleotide polymorphisms (rs2261612, rs2522138 and rs16950058) on SIRT4 were evaluated. Results: G carriers of rs2261612 were associated with the susceptibility of DCM in codominant, dominantand overdominant genetic models (all p<0.01). Furthermore, the AG/GG and AG genotype of rs2261612 in dominant and overdominant models correlated with poor prognosis of DCM, independent of left ventricular ejection fraction and cardiac resynchronization therapy (p<0.001). Conclusion:SIRT4 polymorphisms were associated with the susceptibility and prognosis of DCM in a Chinese population.

Association between CDK8 gene polymorphisms and dilated cardiomyopathy in a Chinese Han population.

Dilated cardiomyopathy (DCM) is one of the most common types of cardiomyopathies. Various genes have been verified to be related to DCM, but the pathogenesis remains unclear. Cyclin-dependent-kinase 8 (CDK8), encoded by the CDK8 gene, is a transcriptional factor that regulates the phosphorylation of RNA polymerase II. It plays an important role in the transcription process and different signaling pathways. This study aimed to investigate the potential role of CDK8 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population. Two single nucleotide polymorphisms (SNPs) of CDK8, rs17083838 (A/G) and rs7992670 (A/G), were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 341 DCM patients and 381 healthy controls. Survival analysis was performed using Kaplan-Meier curves and Cox regression analysis. The frequencies of allele A of both SNPs rs17083838 and rs7992670 were increased in DCM patients compared to healthy controls (P<0.05). Genotypic frequencies of rs17083838 and rs7992670 were associated with the susceptibility to DCM in the codominant, and recessive models (P<0.05), and AA/AG genotypes of rs17083838 were also related to DCM susceptibility in the dominant model. AA/AG genotypes of rs17083838 and the AA genotype of rs7992670 in the dominant and recessive genetic models presented a correlation with the poor prognosis of DCM patients in both univariate (P<0.05) and multivariate analyses (P<0.05) after adjusting for age, gender, left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF). This research is the first to reveal that CDK8 gene polymorphisms might be related to DCM susceptibility and prognosis in the Chinese Han population.

Associations between TAB2 gene polymorphisms and dilated cardiomyopathy in a Chinese population.

Aim: The present study aimed to investigate the role of TAB2 gene polymorphisms in dilated cardiomyopathy (DCM) susceptibility and prognosis in a Chinese population. Materials & methods: A total of 343 DCM patients and 451 controls were enrolled and had their blood genotyped. Survival analysis was evaluated with Kaplan-Meier curves and Cox regression analysis. Results: G carriers (AG/GG) and AG genotype of rs237028 had a higher DCM susceptibility as well as a worse DCM prognosis. Additionally, C carriers (CT/CC) of rs652921 and G carriers (TG/GG) of rs521845 had a higher DCM risk and CC homozygote of rs652921 had a worse DCM prognosis. These associations were still significant after adjustment for the Bonferroni correction. Conclusion:TAB2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese population.

Association Between AXIN1 Gene Polymorphisms and Dilated Cardiomyopathy in a Chinese Han Population.

Dilated cardiomyopathy (DCM) is a common type of cardiomyopathy. The pathogenesis of DCM remains unclear and involves varied genes. AXIN1 is a crucial gene in regulating various functions in cells, it encodes protein Axin1, which regulates the assembly and disassembly of β-catenin destruction complex. In addition, Wnt/β-catenin signaling pathway plays an important role in cardiogenesis. We aimed to detect whether AXIN1 polymorphisms contribute to the susceptibility and prognosis of DCM in a Chinese Han population. A total of 340 DCM patients and 430 controls were enrolled, and patients who had complete contact information were followed up for a median period of 49 months. Polymerase chain reaction-restriction fragment length polymorphism was carried out to genotype the two AXIN1 tag single nucleotide polymorphisms (SNPs) (rs12921862 and rs1805105). All data were analyzed using the statistical software package, SPSS 21.0. The frequencies of allele A in rs12921862 and allele C in rs1805015 were increased in DCM patients compared with healthy controls (p < 0.001). Genotypic frequencies of rs12921862 and rs1805105 were associated with the susceptibility of DCM in codominant, dominant, and overdominant models (p < 0.01). AA/AC and AC genotypes of rs12921862 in the dominant and the overdominant genetic models also presented a correlation with poor prognosis of DCM in both univariate (p < 0.01) and multivariate analyses (p < 0.01) after adjusting for age, gender, left ventricular (LV) end-diastolic diameter, and LV ejection fraction. Our results suggest that AXIN1 polymorphisms are associated with the susceptibility and prognosis of DCM in a Chinese Han population.

Association between rs1800629 polymorphism in tumor necrosis factor-α gene and dilated cardiomyopathy susceptibility: Evidence from case-control studies.

Objective:Several published studies have investigated the association between the −308G/A (rs1800629) polymorphism in the tumor necrosis factor-α (TNF-α) gene and the risk of dilated cardiomyopathy (DCM). However, the TNF-α gene polymorphism has a controversial role in the pathogenesis of DCM among different populations. In the present study, a meta-analysis was performed to resolve this inconsistency.Methods:Potentially eligible papers reporting an association between the TNF-α rs1800629 polymorphism and DCM susceptibility were searched in 4 databases including PubMed, EMBASE, Chinese Biomedical Database (CBM), and the Cochrane Library up to April 1, 2018. The odds ratio (OR) with its 95% confidence interval (CI) was used to estimate the strength of the associations. Subgroup analysis based on the ethnicity, studies with or without ischemic and valvular DCM was conducted. Publication bias detection was conducted using Begg test.Results:Nine papers detailing case-control studies were included, reporting a total of 1339 DCM cases and 1677 healthy controls. The meta-analysis results indicated that TNF-α rs1800629 was associated with increased DCM susceptibility in the populations studied under the heterozygous model (AG vs GG: OR = 1.91, 95% CI = 1.05−3.50, P = .035) and dominant model (AG + AA vs GG: OR = 1.87, 95% CI = 1.01−3.45, P = .046). In the subgroup analysis for ethnicity, rs1800629 polymorphism was significantly associated with the susceptibility of DCM for Asians under the 5 models (A vs G: OR = 2.87, 95% CI = 1.56−5.30, P = .001; AA vs GG: OR = 3.95, 95% CI = 1.13−13.82, P = 0.031; AG vs GG: OR = 3.8, 95% CI = 1.57−9.19, P = .003; AA vs GG + AG: OR = 2.51, 95% CI = 1.41−4.49, P = .002; AG + AA vs GG: OR = 3.77, 95% CI = 1.54−9.20, P = .004).Conclusion:There may be a moderate association between TNF-α rs1800629 polymorphism and DCM susceptibility in the whole populations studied; however, TNF-α rs1800629 polymorphism was significantly associated with the susceptibility of DCM for Asians, which indicates that such associations may be different between ethnicities.

Influence of LGALS3 gene polymorphisms on susceptibility and prognosis of dilated cardiomyopathy in a Northern Han Chinese population

BackgroundGalectin-3 plays an important role in modulating cardiac inflammation and fibrosis. It also takes part in the pathways underlying cardiac remodeling. Therefore, LGALS3 gene, encoding galectin-3 protein, is a promising candidate for the genetic study of dilated cardiomyopathy (DCM). To date, there has been no research evaluating the association between LGALS3 gene polymorphisms and the susceptibility and prognosis of DCM. Methods and ResultsGenotyping of 4 single nucleotide polymorphisms (SNPs) in the LGALS3 gene, which were reported to be functional in the literature, was performed in 279 unrelated clinically diagnosed DCM patients and 363 apparently healthy controls from Northern Han Chinese population using iPLEX SNP Genotyping analysis on a Sequenom MassARRAY System. The frequency of G allelic polymorphism of rs1009977 and the C allelic polymorphism of rs4652 were lower in DCM patients (OR=0.77, 95% CI [0.60–0.99], P=0.045; OR=0.79, 95% CI [0.63–0.99], P=0.042, respectively). The minor variants of rs1009977 and rs4652 were associated with low susceptibility of DCM under additive genetic models (P=0.045 and P=0.040, respectively). The AA genotype of both rs2274273 and rs4644 was associated with lower left ventricular ejection fraction (recessive model, P=0.018 for both; additive model, P=0.039 for both). The G variant of rs1009977 was related with lower serum galectin-3 level in DCM patients under three genetic models (additive model, P=0.020, dominant model, P=0.020, recessive model, P=0.037). The A variant of both rs2274273 and rs4644 was associated with lower level of galectin-3 in DCM patients under additive model (P=0.032 for both) and dominant model (P=0.012 for both). None of the 4 SNPs was associated with the cardiovascular or all-cause death rate of DCM. In Conclusion, LGALS3 gene polymorphisms might be associated with the susceptibility of DCM in a Northern Han Chinese population.

IL-27 genetic variation and susceptibility of dilated cardiomyopathy in Chinese Han population.

Accumulating data showed that IL-27 polymorphisms are linked to the susceptibility of some autoimmune diseases. We assessed whether there was an association between two single nucleotide polymorphisms (SNPs) of IL-27 gene and dilated cardiomyopathy (DCM). Two SNPs (rs153109 and rs17855750) of IL-27 gene were genotyped by PCR-restriction fragment length polymorphism in 261 DCM patients and 303 unrelated healthy subjects in Chinese Han population. Compared with controls, our results showed that SNP rs153109 displayed significant associations with DCM in Chinese Han population, whereas no differences in genotype or allele frequencies were found between DCM patients and controls at SNP rs17855750. Our study showed that, for the first time, the association of the IL-27 gene SNP with the patients with DCM.

Associations between Interleukin-31 Gene Polymorphisms and Dilated Cardiomyopathy in a Chinese Population.

To explore the role of Interkeulin-31 (IL-31) in dilated cardiomyopathy (DCM), in our study, two SNPs of IL-31, rs4758680 (C/A) and rs7977932 (C/G), were analyzed in 331 DCM patients and 493 controls in a Chinese Han population. The frequencies of C allele and CC genotype of rs4758680 were significantly increased in DCM patients (P = 0.005, P = 0.001, resp.). Compared to CC genotype of rs4758680, the A carriers (CA/AA genotypes) were the protect factors in DCM susceptibility while the frequencies of CA/AA genotypes were decreased in the dominant model for DCM group (P < 0.001, OR = 0.56, 95%CI = 0.39–0.79). Moreover, IL-31 mRNA expression level of white blood cells was increased in DCM patients (0.072 (0.044–0.144) versus 0.036 (0.020–0.052), P < 0.001). In survival analysis of 159 DCM patients, Kaplan-Meier curve revealed the correlation between CC homozygote of rs4758680 and worse prognosis for DCM group (P = 0.005). Compared to CC genotype, the CA/AA genotypes were the independent factors in both univariate (HR = 0.530, 95%CI = 0.337–0.834, P = 0.006) and multivariate analyses after age, gender, left ventricular end-diastolic diameter, and left ventricular ejection fraction adjusted (HR = 0.548, 95%CI = 0.345–0.869, P = 0.011). Thus, we concluded that IL-31 gene polymorphisms were tightly associated with DCM susceptibility and contributed to worse prognosis in DCM patients.

Associations Between TIM1 Polymorphisms and Dilated Cardiomyopathy in a Han Chinese Population.

Immune dysfunction is implicated in dilated cardiomyopathy (DCM). Previous studies found that TIM1 polymorphisms were associated with immune dysfunction. However, the associations between TIM1 polymorphisms and DCM have not been investigated. Therefore, we conducted the present study to evaluate whether TIM1 polymorphisms were associated with DCM in the Han Chinese population. A total of 396 DCM patients and 403 healthy controls were enrolled in this case-control study. Two promoter region single nucleotide polymorphisms (SNPs) of TIM1 gene, -416G>C and -1454G>A, were genotyped by PCR-RFLP. The associations between two SNPs genotyped and the overall survival (OS) of DCM patients were evaluated with Kaplan-Meier analysis and Cox regression analysis. Plasma TIM-1 levels were further measured by ELISA. We found that the C allelic frequency of -416G>C and A allelic frequency of -1454G>A were higher in DCM patients than that in controls (P < 0.001). The genotypic frequencies of both SNPs were associated with DCM susceptibility in the codominant, dominant, and overdominant models (P < 0.01). They were also associated with the OS of DCM patients in the dominant, recessive, and overdominant models (P < 0.001). The CC genotype of -416G>C and AA genotype of -1454G>A were associated with the worst prognosis (P < 0.001). In addition, the plasma TIM-1 levels in DCM patients were higher than that in controls (259.0 pg/mL versus 149.8 pg/mL, P = 0.035). The CC genotype of 416G>C and AA genotype of -1454G>A were associated with the highest TIM-1 production (P < 0.01). Overall, our findings suggest that TIM1 polymorphisms are associated with DCM susceptibility and prognosis in this Han Chinese population.

Impact of Angiotensin I Converting Enzyme Insertion/Deletion Polymorphisms on Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy Risk

BackgroundGenetic factors in the pathogenesis of cardiomyopathies have received a lot attention during the past two decades. Angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphisms were found to be associated with cardiomyopathies. However, the previous results were inconsistent. The current meta-analysis aims to examine the association of ACE I/D polymorphisms and dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM).MethodsEight studies on DCM (1387 controls and 977 patients) and eight studies on HCM (1055 controls and 827 patients) were included in this meta-analysis.ResultsThe overall data showed no significant association between ACE I/D polymorphism and DCM risk. Further subgroup analysis by ethnicity also did not find a significantly increased risk for D allele carriers among East Asians and Europeans. However, the overall analysis suggested that the D allele carriers might be associated with increased risk of HCM (DD/ID vs. II: OR = 1.69, 95% CI 1.04–2.74, P = 0.03).ConclusionIn summary, the meta-analysis indicated that certain ACE I/D polymorphism might be associated with HCM but not DCM susceptibility. Given the limited sample sizes, further large multicenter case-control investigation is needed.

Polymorphisms of presenilin-1 gene associate with dilated cardiomyopathy susceptibility

Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. It is the third leading causes of heart failure and the most common cause of heart transplantation due to its ventricular dilatation and contractile dysfunction. Currently, four hypothesized pathogenic mechanisms have been proposed: genetic predisposition, persistent cardiotropic viral infection, autoimmunity, and cell apoptosis. Presenilin-1 gene has been previously found to be associated with cell apoptosis and cardiac development. To assess the role of presenilin-1 in DCM, we examined two single nucleotide polymorphisms (SNPs) in presenilin-1 gene, namely, rs1800844 and rs177415. A total of 282 DCM patients and 306 controls were included in the study, and all SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Compared with controls, the frequency of AA and AC genotypes and the A allele at SNP rs177415 were significantly increased in DCM patients. No difference of the SNP genotype and allele frequencies at SNP rs1800844 was detected between DCM and control groups. Unconditional logistic regression adjusting for type 2 diabetes, hyperlipidemia, cigarette smoking, and gender, confirmed the association between that SNP rs177415 of the presenilin-1 gene and the susceptibility of DCM (adjusted OR 1.300, 95% CI 1.013-1.669; P=0.039). Our data indicate, for the first time, the association of the presenilin-1 gene SNPs with human DCM and the allele A at SNP rs177415 in presenilin-1 gene may increase the risk of DCM.

Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.

Analysis of Adiponectin Gene Polymorphisms in Dilated Cardiomyopathy in a Han Chinese Population

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. The pathogenesis of DCM has been extensively studied for many years, but it remains elusive. Adiponectin is an adipocyte-derived cytokine with anti-inflammatory, antidiabetic, and antiatherogenic properties. To assess the role of adiponectin in DCM, we examined two single-nucleotide polymorphisms in the adiponectin gene, rs1501299 and rs2241766. A total of 203 DCM patients and 258 control subjects were recruited in this study and all single-nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. No statistically significant differences in genotype and allele frequencies were observed between DCM and controls with any of the adiponectin genetic variants. These data may provide evidence that adiponectin polymorphisms do not play a role in the susceptibility of DCM in the Han Chinese population.

Interleukin‐23 receptor gene polymorphisms is associated with dilated cardiomyopathy in Chinese Han population

Idiopathic dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. The pathogenesis of DCM has been extensively investigated for many years, but it remains uncertain. Recently, many studies indicated that autoimmune mechanisms are likely to participate in the pathogenesis of DCM. Interleukin-23 receptor (IL-23R) gene polymorphisms have been previously found to be associated with autoimmune diseases. To assess the role of IL-23R in DCM, we examined three single nucleotide polymorphisms (SNPs) in IL-23R gene, namely, rs1884444, rs11465817 and rs10889677. A total of 176 DCM patients and 216 controls were included in the study, and all SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Our results showed that SNP rs10889677, but not rs1884444 and rs11465817, had association with DCM in Chinese Han population. The results suggest that IL-23R polymorphisms appear to play an important role in the susceptibility of DCM in Chinese Han population.

Functional Consequences of Hypertrophic and Dilated Cardiomyopathy-causing Mutations in α-Tropomyosin

To study the functional consequences of various cardiomyopathic mutations in human cardiac alpha-tropomyosin (Tm), a method of depletion/reconstitution of native Tm and troponin (Tn) complex (Tm-Tn) in cardiac myofibril preparations has been developed. The endogenous Tm-Tn complex was selectively removed from myofibrils and replaced with recombinant wild-type or mutant proteins. Successful depletion and reconstitution steps were verified by SDS-gel electrophoresis and by the loss and regain of Ca2+-dependent regulation of ATPase activity. Five Tm mutations were chosen for this study: the hypertrophic cardiomyopathy (HCM) mutations E62Q, E180G, and L185R and the dilated cardiomyopathy (DCM) mutations E40K and E54K. Through the use of this new depletion/reconstitution method, the functional consequences of these mutations were determined utilizing myofibrillar ATPase measurements. The results of our studies showed that 1) depletion of >80% of Tm-Tn from myofibrils resulted in a complete loss of the Ca2+-regulated ATPase activity and a significant loss in the maximal ATPase activity, 2) reconstitution of exogenous wild-type Tm-Tn resulted in complete regain in the calcium regulation and in the maximal ATPase activity, and 3) all HCM-associated Tm mutations increased the Ca2+ sensitivity of ATPase activity and all had decreased abilities to inhibit ATPase activity. In contrast, the DCM-associated mutations both decreased the Ca2+ sensitivity of ATPase activity and had no effect on the inhibition of ATPase activity. These findings have demonstrated that the mutations which cause HCM and DCM disrupt discrete mechanisms, which may culminate in the distinct cardiomyopathic phenotypes.