Dataset Information

A Haplotype of Two Novel Polymorphisms in ?-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.

ABSTRACT: The role of genetic abnormality of ?-sarcoglycan (?-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in ?-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100~-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c.-100~-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c.-100~-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38-9.55; p = 0.44). Co-occurrence of the genotypes -/- of c.-100~-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C.-100~-110 resulted in a decrease of ?-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that ?-SG-283R interacts normally to ?- and ?-SG, but significantly decreased localization of ?/?/?-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.

SUBMITTER: Chen J

PROVIDER: S-EPMC4697846 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.

Chen Jie J Jin Ye Y Wang Hong H Wei Sisi S Chen Dan D Ying Li L Zhou Qing Q Li Gang G Li Joyce J Gao Jimin J Kato Naoya N Hu Wei W Li Yigang Y Wang Yuepeng Y

PloS one 20151231 12

The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100~-110; -) in the promoter regio ...[more]

PMID: 26720722

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Project description:AimsDilated 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.Methods and resultsA total of 600 idiopathic DCM patients and 700 healthy controls were enrolled. Patients with contact information were followed up for a median period of 28 months. 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.ConclusionsOur study suggested that MMP2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese Han population.

Project description:Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T-786C of the 5' flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p?=?0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34-3.27, p?=?0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p?=?0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM phenotype.

Project description:BackgroundPrevious observational studies have shown intimate associations between fatty acids (FAs) and dilated cardiomyopathy (DCM). However, due to the confounding factors and reverse causal association found in observational epidemiological studies, the etiological explanation is not credible.ObjectiveTo exclude possible confounding factors and reverse causal associations found in observational epidemiological studies, we used the two-sample Mendelian randomization (MR) analysis to verify the causal relationship between FAs and DCM risk.MethodAll data of 54 FAs were downloaded from the genome-wide association studies (GWAS) catalog, and the summary statistics of DCM were extracted from the HF Molecular Epidemiology for Therapeutic Targets Consortium GWAS. Two-sample MR analysis was conducted to evaluate the causal effect of FAs on DCM risk through several analytical methods, including MR-Egger, inverse variance weighting (IVW), maximum likelihood, weighted median estimator (WME), and the MR pleiotropy residual sum and outlier test (MRPRESSO). Directionality tests using MR-Steiger to assess the possibility of reverse causation.ResultsOur analysis identified two FAs, oleic acid and fatty acid (18:1)-OH, that may have a significant causal effect on DCM. MR analyses indicated that oleic acid was suggestively associated with a heightened risk of DCM (OR = 1.291, 95%CI: 1.044-1.595, P = 0.018). As a probable metabolite of oleic acid, fatty acid (18:1)-OH has a suggestive association with a lower risk of DCM (OR = 0.402, 95%CI: 0.167-0.966, P = 0.041). The results of the directionality test suggested that there was no reverse causality between exposure and outcome (P < 0.001). In contrast, the other 52 available FAs were discovered to have no significant causal relationships with DCM (P > 0.05).ConclusionOur findings propose that oleic acid and fatty acid (18:1)-OH may have causal relationships with DCM, indicating that the risk of DCM from oleic acid may be decreased by encouraging the conversion of oleic acid to fatty acid (18:1)-OH.

Dataset Information

A Haplotype of Two Novel Polymorphisms in ?-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.

Publications

A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.

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