scholarly journals Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

2012 ◽  
Vol 72 (7) ◽  
pp. 1233-1238 ◽  
Author(s):  
Lina-Marcela Diaz-Gallo ◽  
Carmen P Simeon ◽  
Jasper C Broen ◽  
Norberto Ortego-Centeno ◽  
Lorenzo Beretta ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Genetic Susceptibility ◽  
Interleukin 2 ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination ◽  
Single Nucleotide ◽  
Cutaneous Form ◽  
Caucasian Patients

ObjectiveThe interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc).Patients and methodsThe case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays.ResultsWe observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively).ConclusionsThese results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.

scholarly journals Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis

2010 ◽  
Vol 70 (3) ◽  
pp. 454-462 ◽  
Author(s):  
LM Diaz-Gallo ◽  
P Gourh ◽  
J Broen ◽  
C Simeon ◽  
V Fonollosa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Meta Analysis ◽  
The Novel ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination Assay ◽  
Allelic Discrimination ◽  
Single Nucleotide ◽  
Independent Replication ◽  
First Time

ObjectiveTwo functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.Methods3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc.ResultsThe meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (pFDRcorrected=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (pFDRcorrected=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (pFDRcorrected=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).ConclusionThe study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

scholarly journals NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis

2010 ◽  
Vol 70 (4) ◽  
pp. 668-674 ◽  
Author(s):  
P Dieudé ◽  
M Guedj ◽  
J Wipff ◽  
B Ruiz ◽  
G Riemekasten ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Systemic Sclerosis ◽  
Potential Role ◽  
Additive Model ◽  
Nucleotide Polymorphisms ◽  
Fibrosing Alveolitis ◽  
Single Nucleotide ◽  
Risk Alleles ◽  
Caucasian Origin

BackgroundRecent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1β. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders.ObjectiveTo study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population.MethodsNLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin.ResultsConditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA.ConclusionsOur results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

scholarly journals Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis

2009 ◽  
Vol 69 (3) ◽  
pp. 550-555 ◽  
Author(s):  
Pravitt Gourh ◽  
Frank C Arnett ◽  
Filemon K Tan ◽  
Shervin Assassi ◽  
Dipal Divecha ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Costimulatory Molecule ◽  
Susceptibility Gene ◽  
Potential Interaction ◽  
Gene Region ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Ox40 Ligand

ObjectiveIt is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.MethodsA total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.ResultsCase-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.ConclusionsPolymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.

scholarly journals Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis

2011 ◽  
Vol 71 (1) ◽  
pp. 114-119 ◽  
Author(s):  
F David Carmona ◽  
Ramana Gutala ◽  
Carmen P Simeón ◽  
Patricia Carreira ◽  
Norberto Ortego-Centeno ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Meta Analysis ◽  
Conditional Logistic Regression ◽  
Statistical Significance ◽  
Genomic Region ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination ◽  
Autoantibody Production

ObjectiveSystemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.MethodsTwo case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc.ResultsFour out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: pFDR=6.14 × 10−4, OR=0.78; rs4963128: pFDR=6.14 × 10−4, OR=0.79; rs702966: pFDR=3.83 × 10−3, OR=0.82; and rs2246614: pFDR=3.83 × 10−3, OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant.ConclusionsThe results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.

Association of HLA Class II Genes with Systemic Sclerosis in Spanish Patients

2009 ◽  
Vol 36 (12) ◽  
pp. 2733-2736 ◽  
Author(s):  
CARMEN P. SIMEÓN ◽  
VICENT FONOLLOSA ◽  
CARLES TOLOSA ◽  
EDUARD PALOU ◽  
ALBERT SELVA ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Genetic Susceptibility ◽  
Topoisomerase I ◽  
Chain Reaction ◽  
Clinical Expression ◽  
Caucasian Patients ◽  
Pulmonary Arterial ◽  
Polymerase Chain

Objective.To examine the role of HLA-DRB1 and HLA-DQB1 alleles in the susceptibility to systemic sclerosis (SSc) and its clinical expression in a Spanish population.Methods.One hundred Spanish Caucasian patients with SSc and 130 controls were studied. Molecular HLA-DRB1 and HLA-DQB1 typing was performed by polymerase chain reaction (PCR) sequence-based typing and PCR sequence-specific oligonucleotide.Results.HLA-DRB1*11 was associated with genetic susceptibility to SSc, whereas HLA-DRB1*07 (HLA-DRB1*0701) showed a protective effect. A significant increase in the frequency of the DRB1*1104 allele was observed in patients with anti-topoisomerase I autoantibodies (anti-Topo I) while HLA-DRB1*01 and HLA-DQB1*05 alleles were significantly increased in patients with anti-centromere antibodies (ACA). The HLA-DRB1*11 allele was more frequent in patients with pulmonary fibrosis; however, no significant association with any HLA-DRB1 or DQB1 alleles was identified in patients with pulmonary arterial hypertension.Conclusion.HLA alleles play a role in genetic susceptibility to SSc in Spanish patients. Some alleles are more prevalent in patients with pulmonary fibrosis and in patients with certain SSc-specific autoantibodies (anti-Topo I and ACA).

scholarly journals Association Study of Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 and 2 Genes in Iranian Women with Preeclampsia

2019 ◽  
Author(s):  
Hamid DARGAHI ◽  
Mohammad Hossein NICKNAM ◽  
Mahroo MIRAHMADIAN ◽  
Mahdi MAHMOUDI ◽  
Saeed ASLANI ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Single Nucleotide Polymorphisms ◽  
Case Control Study ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination ◽  
Single Nucleotide ◽  
Genotype Frequencies ◽  
Control Study ◽  
Risk Of Preeclampsia

Background: Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and 2) are involved in blood pressure regulation and single nucleotide polymorphisms (SNPs) of these genes have been linked to preeclampsia. This study intended to assess the association of ERAP1 and 2 genes polymorphism with Iranian preeclamptic women. Methods: In this case-control study, 148 preeclamptic and 133 pregnant women were selected from the Kosar Hospital, Qazvin, Iran, during 2013-2015. In order to genotype the subjects for rs28096, rs30187, rs26653, rs3734016, rs34750 and rs2549782, rs17408150 for ERAP1 and 2 genes, respectively, Real-Time PCR allelic discrimination approach was exploited. Results: Neither allelic nor genotype frequencies of all seven polymorphisms were significantly different between two groups. Though, ACGACTT and GTCAGGA haplotypes were related with decreased (P=0.0079, OR=0.559, 95% CI: 0.363-0.861 and P=0.02, OR=0.417, 95% CI: 0.194-0.896, respectively), but ACGACGT and GTGACTT haplotypes were associated with an increased (P=0.00082, OR=3.657, 95% CI: 1.630-8.206 and P=0.02, OR=2.401, 95% CI: 1.119-5.151, respectively) risk of preeclampsia. Moreover, some positions were detected to be in linkage disequilibrium. Conclusion: Ongoing investigation resulted differently from before performed studies considering the role of ERAP1 and ERAP2 gene polymorphisms in predisposing women to preeclampsia, emphasizing on the genetic structure differences among various racial populations.

Association of PER2 gene single nucleotide polymorphisms with genetic susceptibility to systemic lupus erythematosus

Lupus ◽  
2021 ◽  
pp. 096120332198979
Author(s):  
Yi-Lin Dan ◽  
Chan-Na Zhao ◽  
Yan-Mei Mao ◽  
Qian Wu ◽  
Yi-Sheng He ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Single Nucleotide Polymorphisms ◽  
Genetic Susceptibility ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Nucleotide Polymorphisms ◽  
Systemic Lupus ◽  
Single Nucleotide ◽  
Period 2

The circadian clock plays a crucial role in the progress of systemic lupus erythematosus (SLE). In this study, we performed a case-control study to explore the association between Period 2 (PER2) gene single nucleotide polymorphisms (SNPs) and the susceptibility of systemic lupus erythematosus (SLE). A total of 492 SLE patients and 493 healthy controls were included. The improved multiple ligase detection reaction (iMLDR) was used for genotyping. The correlations between four SNPs of PER2 (rs10929273, rs11894491, rs36124720, rs934945) and the genetic susceptibility and clinical manifestations of SLE were analyzed. Significant differences were observed in the distributions of allele frequencies and genotype under dominant model in rs11894491 between SLE patients and controls ( p = 0.030, p = 022, respectively). We hypothesized that PER2 gene SNPs was related to the genetic susceptibility and clinical manifestations, implying the potential role of PER2 in the pathogenesis of SLE.

scholarly journals Association of interleukin 2, interleukin 12, and interferon-γ with intervertebral disc degeneration in Iranian population

2020 ◽  
Author(s):  
Sara Hanaei ◽  
Sina Abdollahzade ◽  
Maryam Sadr ◽  
Mohammad Hossein Mirbolouk ◽  
Ehsan Fattahi ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Interleukin 2 ◽  
Interleukin 12 ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Ifn Γ

Abstract Background: Intervertebral disc degeneration (IVDD) is an age-related degenerative disease, presenting low back pain or radicular pain in a variety of severity. As the inflammatory changes in discs, the inflammatory and anti-inflammatory cytokines, as well as their respective genes, have been proposed to play role in pathophysiology of disease. This study has been conducted to elucidate the role of IL-2, IL-12, and IFN-γ single nucleotide polymorphisms (SNP) in this disease.Method: 76 patients diagnosed with IVDD and 140 healthy subjects who have complied with eligibility criteria have been included. A total volume of 5cc peripheral blood of each participant has been used for investigating the IL-2 +166G/T, IL-2 -330G/T, IL-12 -1188A/C, and IFN-γ +847A/T single nucleotide polymorphisms (SNP) through PCR-SSP method.Results: The ‘TG’ and ‘TT’ genotypes of IL-2 -330G/T polymorphism have been significantly more common among patients and healthy controls respectively and therefore were associated with disease. The ‘GT’ and ‘TT’ haplotypes of IL-2, comprised of -330G/T, and +166G/T, have been also more common among patients and controls respectively.Conclusion: This study has indicated significant role of IL-2 genotypes and haplotypes in IVDD, as they have been differently distributed in cases and controls. Therefore, alteration in IL-2 gene structure could play an important role in pathophysiology of IVDD through alteration of its function.

scholarly journals Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts

2011 ◽  
Vol 38 (6) ◽  
pp. 1033-1038 ◽  
Author(s):  
BAPTISTE COUSTET ◽  
SANDEEP K. AGARWAL ◽  
PRAVITT GOURH ◽  
MICKAEL GUEDJ ◽  
MAUREEN D. MAYES ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Disease Risk ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Risk Genes ◽  
The Usa ◽  
Study Population ◽  
Hardy Weinberg Equilibrium

Objective.Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.Methods.SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort.Results.The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls.Conclusion.These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes.

Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

2020 ◽  
Vol 60 (12) ◽  
pp. 898-903
Author(s):  
Lyudmila P. Kuzmina ◽  
Anastasiya G. Khotuleva ◽  
Evgeniy V. Kovalevsky ◽  
Nikolay N. Anokhin ◽  
Iraklij M. Tskhomariya
Keyword(s):  
Antioxidant Enzymes ◽  
Genetic Polymorphism ◽  
Genetic Predisposition ◽  
Risk Groups ◽  
Dust Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Gstp1 Gene ◽  
Polymorphic Variants

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

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