Association of polymorphisms within the promoter region of the tumor necrosis factor-α with clinical outcomes of rheumatic fever (original) (raw)
Related papers
Molecular …, 2007
Rheumatic fever (RF)/rheumatic heart disease (RHD) is an inflammatory disease with a complex etiology in which Group A streptococci within a genetically susceptible host untreated for strep-throat may deviate the innate and adaptive arms of the immune system towards recognition of autoantigens. The TNFA gene has been associated with a number of autoimmune diseases, including RF. We investigated whether the G−308A and G−238A polymorphisms of the TNFA gene are associated with clinical outcomes of RF in a cohort of 318 patients and 281 healthy controls (HC). Both polymorphisms showed borderline associations with RF (TNFA −308G/A, OR = 1.4 [1-2.2], P = 0.026; TNFA −238G/A, OR = 1.9 [1-3.3], P = 0.015). The presence of either one of the minor alleles (−308A and −238A) was more common among patients with RF/RHD than controls (P = 0.0006). Stratification of patients according to clinical phenotype also showed significant associations between presence of either one of the minor alleles and RHD (Pc = 0.0006) when compared with controls. This association was stronger with the development of aortic valve lesions. In contrast, there was no association between genotype and Sydenham's chorea or RF patients with mild carditis. In conclusion, we show that the TNFA is a susceptibility locus for RF. The ability to predict which RF patients will develop valve lesion may have therapeutic, economic and social implications.
Pediatric Cardiology, 2007
Rheumatic heart disease (RHD) is an inflammatory disease of the heart tissues caused by interactive immune, genetic, and environmental factors. The objective of this study is to test for the association of polymorphisms related to cytokine genes with susceptibility and severity of RHD among affected children from the Nile Delta region of Egypt. The study included 50 children with chronic RHD (29 males and 21 females), with a mean age of 12.2 years, in addition to 98 healthy unrelated controls. Cases were further classified on the basis of echocardiographic findings into those with only mitral valve disease (MVD) or multivalvular lesions (MVLs) and also as mild, moderate, or severe valve lesions. For all cases and controls, DNA was extracted and amplified using polymerase chain reaction with sequence-specific primers for detection of single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes tumor necrosis factor (TNF)-a-308 G/A, interleukin (IL)-10-1082 G/A, and IL-6-174 G/C as well as a variable number of tandem repeats (VNTRs) in intron 2 of the IL-1Ra gene. All cases showed a significantly higher frequency of homozygous genotypes of TNFa-308 A/A [odds ratio (OR) = 5.7, p < 0.001], IL-10-1082 A/A (OR = 3.1, p < 0.05), IL-10-1082 G/G (OR = 5.2, p < 0.05), and IL-1Ra A1/A1 (OR = 2.2, p < 0.05). Cases with MVD showed higher frequencies of genotypes TNFa-308 A/A, G/G; IL-10-1082 G/G; and IL-1Ra VNTR A1/A1 (p < 0.05). Cases with MVL showed a significantly higher frequency of homozygous A/A genotype of both TNF-a-308 (OR = 10.6, p < 0.05) and IL-10-1082 (OR = 5.2, p < 0.05). The same was observed for cases with severe valve lesions. On the other hand, all studied groups showed significantly lower frequency of heterozygous genotypes of TNF-a-308 G/A, IL-10-1082 G/A, and IL-1Ra VNTR A1/A2. No significant difference was found regarding the frequency of IL-6-174 G/C polymorphisms in total cases or subgroups compared to controls (p > 0.05). Predisposition to RHD is influenced by genetic factors including cytokine gene polymorphisms, with possible susceptibility to severe disease with multivalvular affection among cases with composite polymorphism (TNF-a-308 A/A and IL-10-1082 A/A) and (TNF-a-308 A/A and IL-10-1082 G/G). Keywords Rheumatic fever Á Cytokines Á Gene polymorphism Á Polymerase chain reaction Á TNF-a Á IL-10 Á IL-6 Á IL-1Ra Rheumatic fever is expressed as an inflammatory reaction that involves many organs, primarily the heart, the joints, and the central nervous system. The clinical manifestation of acute rheumatic fever (ARF) represents an abnormal host response following group A streptococcal infection of the tonsillopharynx. The major importance of ARF is its ability to cause fibrosis of heart valves, leading to crippling chronic rheumatic heart disease (RHD) [8]. Studies on individual host response together with the observation of familial incidence of the disease suggest that
Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with rheumatic heart disease
Journal of Autoimmunity, 2003
The major histocompatibility (MHC) genes including TNF-␣, HSP70 and HLA genes have been associated with systemic lupus erythematosus (SLE) in several populations. In this study we analyze the polymorphism of TNF-␣ promoter in 51 Mexican Mestizo SLE patients and 55 ethnically-matched healthy controls by polymerase chain reaction methods. No statistically significant differences were observed in the TNF −308 allele and genotype distribution between patients and healthy controls. However, we found a significant increase in the TNF G/A −238 genotype and in the TNFA −238 allele frequencies in the SLE group when compared with healthy controls (Pc = 0.03, OR = 4.77 and Pc = 0.02, OR = 3.62, respectively). DRB1 analysis showed a similar distribution in patients and controls. Linkage disequilibrium was observed for five haplotypes: DRB1*1401-TNFA−238 (D = 0.84; DЈ = 1.0; P = 0.015); DRB1*0301-TNFA−238 (D = 1.38; DЈ = 0.41; P = 0.042); DRB1*1106-TNF2−308 (D = 0.9; DЈ = 1.0; P = 0.0006); DRB1*1104-TNF2−308 (D = 0.83; DЈ = 0.45; P = 0.02) and DRB1*1406-TNF2−308 (D = 0.83; DЈ = 0.45; P = 0.02). Our data suggest that the association between the TNF-␣ −238 polymorphism and SLE could play a major role in disease susceptibility. Genes and Immunity (2001) 2, 363-366.
Lack of association of TNFAIP3 polymorphism with rheumatic heart disease in Saudi population
IOSR Journals , 2019
Rheumatic heart disease (RHD) is an autoimmune disease developed subsequently to Streptococcus infection. RHD is still causing acquired heart problems in children in many developing countries. TNFAIP3 encodes the ubiquitin-modifying enzyme (A20), an important negative regulator in different inflammatory pathways. Polymorphisms in TNFAIP3 have been reported to be associated with several inflammatory diseases. Tagging single nucleotide polymorphisms (tSNP), rs2230926, on chromosome 6q23, have been associated with RHD in Chinese population. In our study we evaluated the association of TNFAIP3 tSNP rs2230926 with RHD in Saudi population. TNFAIP3 tSNP was studied in 124 RHD patients and 205 controls by TaqMan allelic discrimination assay. Carditis was found in 100% in our patients, while arthritis was found in 53%. The genotype frequency of the polymorphism (TT, TC, and CC) in the control group was 58, 33, and 9%, and in the patient group was 48, 40, and 11%, respectively. There was no significant differences. Furthermore, subgroup analysis for the patients found no significant differences between the subgroups and controls. Our data suggest that TNFAIP3 tSNP rs2230926 examined in this study has no role in predicting the occurrence and severity of RHD in Saudi patients. Running Title: TNFAIP3 polymorphism in Saudi Arabian rheumatic heart disease patients
Atherosclerosis, 2011
Objective: To assess the influence of the TNFA rs1800629 (G > A) polymorphism in the risk of cardiovascular (CV) disease and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Methods: 587 patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were studied. Patients were genotyped for the TNFA rs1800629 polymorphism using predesigned TaqMan single nucleotide polymorphism genotyping assay. Also, HLA-DRB1 genotyping was performed using molecular based methods. Carotid artery intima-media thickness, flow-mediated endotheliumdependent and endothelium independent vasodilatation, used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients. Results: We observed a higher frequency of carriers of the minor allele A among the patients with CV disease (with 37.6% vs. without 27.9%, p = 0.06, OR 1.56 [95% confidence interval-CI 0.95-2.54]). Carriers of the minor allele A exhibited a higher risk of CV events after adjustment for demographic and traditional CV risk factors (p = 0.023, HR 1.72 [95% CI 1.076-2.74]). Also, a significant interaction between this polymorphism and the presence of the rheumatoid shared epitope (SE) was observed (p = 0.024). Due to this, the association between carriers of the minor allele A and CV disease was only present in carriers of the SE, even after adjustment (p = 0.001,. No significant association between the TNFA variant and the surrogate markers of subclinical atherosclerosis was observed. Conclusion: Our results show that TNFA rs1800629 gene polymorphism is associated with predisposition to CV complications in patients with RA. This predisposition is restricted to individuals carrying the rheumatoid SE.
Russian Journal of Cardiology, 2014
Aim. Acute rheumatic fever is an inflammatory disease developing after upper respiratory tract infection with group A streptoccoci and its most important complication is rheumatic heart disease (RHD). Tumor necrosis factor (TNF)-α and interleukin (IL)-1-1082 gene polymorphisms were associated with susceptibility to develop rheumatic heart disease. The aim of our study is to determine the frequency of IL-10-1082 A/G and TNF-α-308 G/A gene polymorphism in Turkish population and to investigate the relationship between these polymorphisms and rheumatic heart disease. Material and Methods. Genotypes of 57 unrelated children with rheumatic heart disease and 99 controls were determined by use of PCR-RFLP. Results. No significant differences were found in genotypes or allele frequencies of TNF-α-308 and IL-10-1082 genes between RHD and control group. There was no relation between TNF-α-308 genotype and allel distribution with valvular involvement (p>0.05). IL-10-1082 GG and AG genotypes were seen more frequent in patients with multiple valvular disease but there was no statistical significance (p>0.05). Conclusion. As a result, there was no relationship between TNF-α-308, IL-10-1082 gene polymorphisms and rheumatic heart disease or valvular involvement in the study population (p>0,05). Our results are thought that TNF-α-308 polymorphisms are silent and may become important only with some certain HLA allels. Further studies checking both cytokine polymorphism and HLA allels are needed.
Association of TNF-α serum levels and TNFA promoter polymorphisms with risk of myocardial infarction
Atherosclerosis, 2006
Elevated levels of tumor necrosis factor-alpha (TNF-␣), and presence of polymorphisms of the TNFA gene have been implicated in cardiovascular disease pathogenesis. We explored the relationship between polymorphisms in the TNFA gene (−1031C/T, −863C/A −857T/C, −308G/A, −238G/A), protein levels of TNF-␣ and their association to myocardial infarction (MI) using a sample of 1213 post-MI patients and 1561 healthy controls. MI risk was higher among men with elevated TNF-␣ levels, with the highest compared to the lowest TNF-␣ quartile giving a 70% risk increase (OR [95% CI]: 1.7 [1.1; 2.6]). Obese subjects who also had elevated TNF-␣ levels were at even higher risk for MI (OR [95% CI]: 3.4 [2.1; 5.6]). Higher TNF-␣ levels were seen among smokers (but not among non-smokers) carrying the −857T allele. Furthermore, a rare haplotype occurred more frequently among the cases than the controls. Elevated TNF-␣ levels are associated with increased MI risk. Obese subjects with elevated TNF-a levels, and carriers of polymorphisms in or near TNFA are particularly susceptible to the hazards of smoking, results which may have implications for cardiovascular preventive measures.
https://www.ijhsr.org/IJHSR\_Vol.12\_Issue.12\_Dec2022/IJHSR-Abstract01.html, 2022
Background: Rheumatic Heart Disease (RHD) is a complex disease, subject to genetic and environmental factors. Cytokines play an important role in development and pathogenesis of the rheumatic heart disease. TNF-α, TGF-β and IL-35 gene polymorphisms may affect the expression levels of cytokines which may lead to damage to the heart valves. Objective: This study was intended to explore the association of TNF-α, TGF-β and IL-35 gene polymorphisms with RHD. Materials and Methods: The present case control study consisted of 145 patients with rheumatic heart disease and 217 control subjects in the same age group. Genotyping was done for the TNF-α (-308), TGF-β-1 (-508) and IL-35(EBI3) gene polymorphisms in both case and control groups. Results: The results showed Bone differences in the distribution of genotypes in TNF-α, TGF-β and IL-35 genes RHD cases and control groups. However, the statistical analysis of the data showed the differences in the genotypes between TNF alpha (-308 G>A), TGF-β-1 (C-508T) and IL-35 EBI3G/C genes RHD case and control subjects were not found to be statistically significant. Conclusion: In conclusion our study could not find any significant association between TNF-α (-308), TGF-β-1 (-508) and IL-35(EBI3) gene polymorphisms and RHD.
Immunology Letters, 2016
Rheumatic heart disease (RHD) is an inflammatory, autoimmune disease; occurring as a consequence of group A streptococcal infection complicated by rheumatic fever (RF). An inappropriate immune response is the central signature tune to the complex pathogenesis of RHD. However, some of those infected develop RHD, and genetic host susceptibility factors are thought to play a key role in diseasedevelopment. Therefore, the present study was designed to explore the role of genetic variants in inflammatory genes in conferring risk of RHD. The study recruited total of 700 subjects, including 400 RHD patients and 300 healthy controls. We examined the associations of 8 selected polymorphisms in seven inflammatory genes: