Association of Genetic Polymorphisms in STAT 3, STAT 5b and GWAS Identified PTPN22 Gene with Rheumatic Heart Disease (original) (raw)
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Clinical and experimental rheumatology
To determine whether the PTPN22, STAT4 and TRAF1/C5 gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction or increased carotid intima-media thickness (IMT) in a series of Spanish patients with rheumatoid arthritis (RA). Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo, and Hospital San Carlos, Madrid, were studied. Patients were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays. Moreover, between March and December 2007, a subgroup of unselected RA patients with no history of CV events was studied for the presence of subclinical atherosclerosis by the assessment of the endothelial function (n=126) and the carotid artery IMT (n=110) by ultrasonography studies. No significant differences in the a...
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
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:
Unfurling the Role of Genetic Polymorphism in Rheumatic Heart Disease Pathogenesis
Rheumatic heart disease (RHD), an autoimmune disease sequel of rheumatic fever, which leads to dysfunction of the heart, is a major public health problem in developing countries that contributes to significant cardiac morbidity and mortality. High mortality was observed in low-income and middleincome countries and even in some groups living in high-income countries. Hence, elucidation of the pathogenic mechanisms in RHD, for therapeutic applications is of major concern and need of the hour. Although, molecular mimicry (MM) is the most established theory for RHD development, however contribution of other factors cannot be ignored. Studies have indicated the role of host-pathogen interacting proteins and immunological factors (T cells-cytokines and chemokines) in RHD, however not much information is available regarding role of polymorphic genes during RHD. The present review, specifically highlights the association of genetic polymorphism with disease manifestation.
Molecular and Cellular Biochemistry, 2013
Rheumatic heart disease (RHD) is one of the most severe consequences of rheumatic fever. It has been suggested that angiotensin I-converting enzyme (ACE) may be involved in the increased valvular fibrosis and calcification in the pathogenesis of RHD. We conducted a case-control study to look for association of ACE I/D polymorphism with RHD in Indian population. The study incorporated 300 patients (170 males and 130 females) with RHD, and 200 controls (118 males and 82 females). We also subgrouped RHD patients into mitral valve lesion (MVL) and combined valve lesion (CVL). ACE I/D polymorphism was identified using polymerase chain reaction method. We also performed a meta-analysis of three published studies and the present study (636 RHD cases and 533 controls) to evaluate the association between the ACE I/D polymorphisms and RHD risk. A significant difference in ACE ID and DD genotypes distribution between RHD cases (OR = 1.62, 95 % CI = 1.11-2.36 and OR = 2.08, 95 % CI = 1.02-4.15, respectively) and corresponding controls was observed. On comparing the ACE genotypes of MVL and CVL subgroups with controls, ID and DD genotypes were also significantly associated with CVL (FDR Pcorr = 0.009, OR = 2.19 and FDR Pcorr = 0.014, OR = 3.29, respectively). Meta-analysis also suggested association of the ACE D allele (FDR Pcorr = 0.036, OR-1.22, 95 % CI 1.02-1.45) with RHD. In conclusion, ACE ID and DD genotypes are associated with an increased risk of RHD, particularly CVL. This suggests that the ACE I/D gene polymorphism may play an important role in the pathogenesis of RHD.
Immunological Investigations, 2018
Background: IL-23/Th17 signaling pathway plays a crucial role in the cell-mediated immune response against bacterial infections and also in the pathogenesis of inflammatory and autoimmune diseases. Recent studies indicate that Th17 cell-associated cytokines are involved in the progression and maintenance of valvular lesions in rheumatic heart disease (RHD). Variants in the genes of cytokines that are potentially involved in Th17 response may influence interindividual differences in their expression levels, thereby contributing to the pathogenesis of immune-mediated diseases such as RHD. Objective: The aim of the study is to investigate the association of IL17A, IL17F, and IL23R gene variants with the risk perception of RHD. Methods: A total of 225 individuals (99 RHD patients and 126 healthy siblings) were recruited for the study. The IL17A (rs2275913), IL17F (rs763780), and IL23R (rs10889677) polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphisms and amplification-refractory mutation system-polymerase chain reaction methods, respectively. Results: The frequency of IL17A (rs2275913) A/A genotype was significantly high in pooled RHD patients (odds ratio [OR] = 2.76; p c = 0.021), rheumatic fever (RF) patients (OR = 14.5; p c = 0.0001), and mitral valvular lesions patients (OR = 2.74; p c = 0.039) when compared to healthy siblings. However, the IL17F (rs763780) and IL23R (rs10889677) polymorphisms did not show any association with RHD. Conclusions: The results suggest that IL17A (rs2275913) polymorphism is associated with the development of RF/RHD in South Indian population. Further studies are required to substantiate the association of these genes with the disease risk.
Pediatric Rheumatology, 2017
Background: Rheumatic heart disease (RHD) is an autoimmune disease where cross reactive CD4 + T cells are involved in the pathogenesis of valvular damage. Human Leukocyte Antigen-G (HLA-G), an immunosuppressive molecule playing a crucial role in the inhibition of T cell response is associated with the pathogenesis of various autoimmune and inflammatory diseases. Genetic polymorphisms within the 3′untranslated region (UTR) of HLA-G influences its expression and thus disease pathogenesis. Hence, the present study aims to unravel the association of 14 bp Ins/Del (rs66554220) and +3142 C/G (rs1063320) polymorphisms in 3′ UTR of HLA-G with RHD. Methods: This familial study consists of 99 RHD families (99 RHD patients, 140 parents and 126 healthy siblings). The 14 bp Ins/Del and +3142 C/G polymorphisms were evaluated by PCR using sequence specific primers and its transmission disequilibrium (TD) was tested by TD test in 70 trio families. Results: The frequency of +3142 C/C genotype was high in patients with combined valvular lesions (CVL) (OR = 5.88; p c = 0.012) and pooled RHD patients (P: OR = 2.76; p = 0.043; p c = 0.076) when compared to healthy siblings. Under the additive (OR = 5.50; p c = 0.026) and recessive genetic model (OR = 5.88; p c = 0.012), the +3142 C/C genotype was significantly associated with CVL in patients. Conclusion: The results suggest that the +3142 C/C genotype may be associated with minor risk for the development of RHD and is more likely to influence the severity of the disease.
Circulation: Genomic and Precision Medicine
Background: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries. Methods: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway. Results: Participants were enrolled into RHDGen between December 2012 and ...
Novel FCN2 Variants and Haplotypes are Associated with Rheumatic Heart Disease
DNA and Cell Biology
Ficolins are pattern recognition molecules that are involved in innate immune defense. Ficonin-2 (FCN2) has a specific affinity for lipoteichoic acid present in the cell wall of Streptococcus pyogenes, an etiological agent for rheumatic heart disease (RHD). We have estimated FCN2 serum levels and analyzed the functional variants of FCN2 in 400 RHD patients, 617 healthy controls, and 581 individuals belonged to various ethnic populations, who are inhabited in various geographical regions of India. Our study revealed that the FCN2-986A and +6359T alleles were the risk factors for RHD susceptibility (p = 0.0007 for-986G>A; p = 0.0004 for +6359C>T). The haplotype AGGT (p = 0.0024) was observed to be a risk factor for RHD susceptibility, and the haplotype GGAC (p = 0.002) was found to confer protection against RHD. The level of serum FCN2 was significantly higher in controls (p < 0.0001) and in controls with GGAC haplotypes (p < 0.0001). The frequency of the risk alleles-986A and +6359T was found to be more prevalent in Northern and NorthWestern (Indo-European) India. The protective GGAC haplotype was found more prevalent in Eastern (Tibeto-Burman) and SouthWestern (Dravidian) India. Alleles-986A and +6359T were in positive correlation with the prevalence of RHD (regression coefficient = 1.84 and 1.94, respectively), whereas GGAC haplotype was in negative correlation with prevalence of RHD (regression coefficient =-1.71). In conclusion, we found that low level of serum ficolin-2 is significantly associated with RHD. Further, FCN2-986A and +6359T alleles and AGGT haplotype are associated with increased susceptibility to RHD, while GGAC haplotype is associated with moderate protection against RHD.
American Heart Journal, 2004
Background Scarring and collagen deposition in the valves and destruction of myocytes may result from the combined effects of a smoldering rheumatic process and a constant trauma to the mitral vlave or aortic valve by the turbulent flow in rheumatic heart disease (RHD). Transforming growth factor-1 (TGF-1) may be responsible for the increased valvular fibrosis and calcification in the pathogenesis of RHD. However, the role of TGF-1 genetic variant in RHD has not been studied. This case-controlled study was carried out to investigate the possible relationship between the TGF-1 gene C-509T and T869C polymorphisms and RHD among the Chinese population in Taiwan. Methods A group of 115 patients with RHD documented by using echocardiography and 100 age-and sexmatched healthy control patients were studied. TGF-1 gene C-509T and T869C polymorphisms were identified with polymerase chain reaction-based restriction analysis. Results A significant difference was seen in the distribution of genotypes between patients with RHD and control patients for either TGF-1 C-509T polymorphism (P Ͻ.0001) or T869C polymorphism (P Ͻ.0001). The frequency of TGF-1 C-509T CC genotype was lower in the RHD group than in the control group (2 ϭ 19.05, P Ͻ.0001), which suggests that this genotype may confer protective effects against RHD. A significant difference was seen in the distribution of allelic frequency between patients with RHD and control patients for TGF-1 T869C polymorphism (P ϭ .04). The odds ratio (OR) for risk of RHD associated with TGF-1 T869C T allele was 1.49 (95% CI, 1.02-2.19). Further categorization of patients with RHD into mitral valve disease and combined valve disease subgroups revealed no statistical difference in these gene polymorphisms when compared with the 2 subgroups. Conclusions Patients with RHD have a lower frequency of TGF-1 C-509T CC genotype and a higher frequency of T869C T allele, which supports a role for the TGF-1 gene C-509T and T869C polymorphisms in determining the risk/ protection of RHD in Taiwan Chinese patients.