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Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy.

ABSTRACT: The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed on activated T cells with downregulatory properties. The aim of this study was to analyse whether single-nucleotide polymorphisms (SNPs) within the CTLA4 gene are associated with the diagnosis and disease course of dilated cardiomyopathy (DCM). In two independent cohorts of DCM patients (n=251 and 223) and healthy controls (n=591), the promoter and all four exons of the CTLA4 gene, including their flanking regions, were genotyped, and the resulting allele and genotype distributions of the identified SNPs were compared between the groups. We confirmed two known SNPs in the promoter region (-318C>T) and in exon 1 (+49A>G;Thr17Ala). The allelic frequencies and genotypic distribution of the promoter SNP were similar for DCM patients compared with controls. However, the G/G genotype of the Thr17Ala variant was significantly more frequent in DCM patients compared with controls (37 out of 251 patients (14.7%) versus 44 out of 591 controls (7.4%), P=0.005). The higher frequency of the G/G genotype was confirmed in an additional DCM cohort (29 out of 223 patients (13.0%), P=0.039), indicating that this SNP functions as a risk factor for DCM. At follow-up after 1 year, the ejection fraction and the end-diastolic diameter of the left ventricle did not differ significantly between DCM patients carrying the G/G genotype versus other genotypes (n=199). Our data indicate that the common CTLA4 variant, Thr17Ala, confers susceptibility for DCM, but does not seem to influence the course of the disease 1 year after diagnosis.

SUBMITTER: Ruppert V

PROVIDER: S-EPMC2987337 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy.

Ruppert Volker V Meyer Thomas T Struwe Clarissa C Petersen Jana J Perrot Andreas A Posch Maximilian G MG Ozcelik Cemil C Richter Anette A Maisch Bernhard B Pankuweit Sabine S

European journal of human genetics : EJHG 20100210 6

The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed on activated T cells with downregulatory properties. The aim of this study was to analyse whether single-nucleotide polymorphisms (SNPs) within the CTLA4 gene are associated with the diagnosis and disease course of dilated cardiomyopathy (DCM). In two independent cohorts of DCM patients (n=251 and 223) and healthy controls (n=591), the promoter and all four exons of the CTLA4 gene, including their flanking regions, ...[more]

PMID: 20145677

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Project description:OBJECTIVE:Several published studies have investigated the association between the -308G/A (rs1800629) polymorphism in the tumor necrosis factor-? (TNF-?) gene and the risk of dilated cardiomyopathy (DCM). However, the TNF-? 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-? 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-? 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-? rs1800629 polymorphism and DCM susceptibility in the whole populations studied; however, TNF-? rs1800629 polymorphism was significantly associated with the susceptibility of DCM for Asians, which indicates that such associations may be different between ethnicities.

Project description:BackgroundEach of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.MethodsAn international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.ResultsFifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.ConclusionsIn the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

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:Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University Aim To evaluate the Association of rs1042713 polymorphism of the ADRB2 gene with dilated idiopathic cardiomyopathy (DCMP) and myocardial dilation of ischemic origin (DMI). Subjects and methods The study included patients with ICMP and DMI in the number of 221 people. The average age of the subjects was in the range of 55.30 ± 9.69 years. We divided the patients into 2 groups: the first – patients diagnosed with idiopathic dilatation cardiomyopathy and the second-patients with myocardial dilatation of ichemic origin. The number of patients in the first group was 111, including 99 men (89.2%) and 12 women (10.8%). The average age of patients in this group is 51.73 ± 9.74 years, in men 51.00 ± 8.96 years, in women 57.75 ± 3.71 years. The second group included patients with myocardial dilatation of ischemic origin. Their number is 110 people, including 100 men (91.5%) and 10 women (8.5%). The average age of respondents is 58.68 ± 8.38 years, for men 58.29 ± 8.46 years, for women 62.90 ± 6.29 years. The control group included patients who had no manifestations of cardiovascular diseases. Their number is 121 people (average age 53.6 ± 4.8 years). The patients underwent laboratory and instrumental studies, as well as molecular and genetic studies of the 16 AG polymorphism of the ADRB2 gene (rs1042713). All patients underwent coronary angiography. Based on the anamnesis data and instrumental studies, those patients who could be said to have no risk factors for the development of dilatation of the heart cavities were identified in the first group. And those patients who were reliably diagnosed with CHD were in the second group, that is, dilatation of the heart cavities is due to a previous myocardial infarction, existing angina pectoris. Results In the group with DCMP 10.8% of patients were carriers of the common homozygous 16AA genotype, the heterozygous 16AG genotype-48.6%, and the rare homozygous 16GG genotype-40.5%. In the control group 11.8% of patients were identified as carriers of a homozygous genotype by a common allele, and 47.5% were carriers heterozygous genotype, and homozygous genotype for a rare allele – 40.7%. The analysis non revealed a statistically significant decrease in the frequency of carrying the homozygous 16GG genotype in patients with DCMP compared to the control group of the rs1042713 polymorphism of the ADRB2 gene. In the group with DM IG, there was no association with the rs1042713 polymorphism of the ADRB2 gene. Conclusion A statistically significant association of rs1042713 of the ADRB2 gene with DCMP was not found. The association of DMI c rs1042713 could not be confirmed.

Dataset Information

Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy.

Publications

Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy.

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