scholarly journals A Functional Haplotype of PADI4 Gene in Rheumatoid Arthritis: Positive Correlation in a French Population

2009 ◽  
Vol 36 (5) ◽  
pp. 881-886 ◽  
Author(s):  
FRÉDÉRIQUE GANDJBAKHCH ◽  
ISABELLE FAJARDY ◽  
BENJAMIN FERRÉ ◽  
SYLVAIN DUBUCQUOI ◽  
RENÉ-MARC FLIPO ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Direct Sequencing ◽  
Susceptibility Gene ◽  
Positive Association ◽  
Arginine Deiminase ◽  
Nucleotide Polymorphisms ◽  
Exon 2 ◽  
Asian Populations ◽  
American College Of Rheumatology ◽  
Elisa Technique

Objective.A functional haplotype of peptidyl arginine deiminase 4 (PADI4) was associated with susceptibility to rheumatoid arthritis (RA) in Asian populations, but the results are contradictory in Europeans. We investigated (1) the association of 2 single-nucleotide polymorphisms (SNP) located in exon 2 of PADI4 with RA in another Caucasian population; and (2) the association between PADI4 and anti-citrullinated protein (anti-CCP) antibodies.Methods.DNA samples were obtained from 405 French RA patients and 275 controls. All RA patients met the revised criteria of the American College of Rheumatology. PADI4_89 163(G→A) and PADI4_90 245(T→C) SNP were genotyped using a PCR-RFLP method confirmed by direct sequencing. All patients and controls were genotyped for HLA-DRB1. The presence of anti-CCP antibodies was tested in 243 RA patients using an ELISA technique.Results.We focused on PADI4_89 163(G→A) and PADI4_90 245(T→C) SNP that distinguished 2 main haplotypes: AC haplotype (PADI4_89*A PADI4_90*C) and GT haplotype (PADI4_89*G PADI4_90*T), described, respectively, as “nonsusceptible” and “susceptible.” A positive association between RA and presence of the GT haplotype was found in the heterozygous state (p = 0.002) and the homozygous state (RA patients 22%, controls 13%; p = 0.005). A correlation was observed between the presence but not the level of anti-CCP antibodies and the GT heterozygous (p = 0.03) and homozygous (p = 0.05) haplotypes. No correlation was found between the HLA-DRB1 shared epitope and any of the PADI4 haplotypes.Conclusion.Our findings confirm those of Japanese, Korean, and Canadian studies and suggest that PADI4 may be a new susceptibility gene independent of HLA-DRB1 for RA in Caucasian populations.

scholarly journals Interleukin 18 gene promoter polymorphisms in Latvian patients with rheumatoid arthritis

2011 ◽  
Vol 65 (1-2) ◽  
pp. 1-6
Author(s):  
Anna Mihailova ◽  
Helena Mikažāne ◽  
Jānis Kloviņs ◽  
Liene Ņikitina-Zaķe
Keyword(s):  
Rheumatoid Arthritis ◽  
Direct Sequencing ◽  
Gene Promoter ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Interleukin 18 ◽  
Promoter Polymorphisms ◽  
Phenotypic Data ◽  
Genome Database ◽  
American College Of Rheumatology

Interleukin 18 gene promoter polymorphisms in Latvian patients with rheumatoid arthritis Interleukin 18 (IL-18) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). There are controversial reports suggesting that IL-18 promoter polymorphisms may be an independent marker of RA susceptibility. The aim of the present study was to determine whether polymorphisms of the IL-18 gene promoter in positions -607 (rs 1946519) and -656 (rs 1946518) are associated with RA, and its characteristics in the Latvian population. We examined 105 patients with RA diagnosed according to the criteria of the American College of Rheumatology. DNA and phenotypic data from a healthy control population was obtained from Genome Database of Latvian Population. Genotypes were obtained by direct sequencing. Single-nucleotide polymorphisms (SNPs) were studied and frequencies of alleles and genotypes were compared between patients and controls. A P value less than 0.05 was accepted as statistically significant. There were no significant differences in the distribution of alleles and genotypes between RA patients and the control group. The frequencies of IL-18-607C/A and -656G/T genotypes differed between patients and the control group in women (P = 0.084 and 0.097). Heterozygous genotypes -607CA and -656GT occurred more frequently in the RA group than in the control (P = 0.046, P = 0.060), and this difference was also significant for the only women groups (P = 0.041,P = 0.054). The heterozygous states -607CA and -656GT of IL-18 gene affect susceptibility to RA. On the basis of investigated IL-18 polymorphisms, female patients with RA seem to represent a separate disease subgroup.

Comparison of the Genetic Structure of Rheumatoid Arthritis Between European and Asian Population

2021 ◽  
Author(s):  
Chun'e Li ◽  
Xiaomeng Chu ◽  
Shiqiang Cheng ◽  
Yan Wen ◽  
Chuyu Pan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Structure ◽  
Genome Wide Association Study ◽  
Inflammatory Diseases ◽  
Enrichment Analysis ◽  
Asian Population ◽  
Arginine Deiminase ◽  
Gene Set Enrichment Analysis ◽  
Asian Populations ◽  
Shared Risk

Abstract Background: Rheumatoid arthritis (RA) is one of the chronic inflammatory diseases that primarily influences the joints, and its prevalence is 0.5-1.0%. Previous studies have shown that there are differences in the genetic structure of RA between European and Asian populations, and most of the studies have been conducted using meta-analysis. This study analyzed the genetic structure of rheumatoid arthritis in European and Asian populations using a new method. Methods: The Genome-Wide Association Study (GWAS) summary statistics of RA from Europe (N=8383) and Asia (N=19190) were derived from an article published in Nature. First, the GWAS data was divided into 1368 blocks, in which SNPs were approximately independent of linkage disequilibrium (LD). Second, we calculated the LD matrix of SNP in each block by using PLINK 1.9. Then, PESCA analysis was performed to detect population-specific/shared risk genes of RA. Finally, Metascape platform was used to perform gene set enrichment analysis. Results: In European population, we found multiple genes which were associated with RA, including HLA-DPA1, HLA-DPB1 (rs2856822, PTP=1.000), MICA (rs2844518, PTP=1.000). In Asian population, C6orf10 (rs3129915, PTP=1.000), PTPN2 (rs2847288, PTP=0.995), were significant related to RA. The population-shared genes included PADI2 (rs2235920, PTP=1.000), STAT4 (rs12612769, PTP=1.000). Furthermore, gene sets enrichment analysis reported population-specific/shared pathway terms, such as interferon-gamma-mediated signaling pathway (P=2.884×10-9), negative regulation of innate immune response (P=1.841×10-7), protein-arginine deiminase activity (P=7.047×10-8). Conclusions: The results of our study indicate differences in risk loci between Asian and European populations, which provided clues for exploring the population-specific/shared genetics and pathogenesis of RA.

Association of RETN and TNFRSF1B polymorphisms with TNF-α inhibitor response in rheumatoid arthritis patients

2020 ◽  
Author(s):  
Nga Thi Trinh ◽  
Hyun Jeong Kim ◽  
Woorim Kim ◽  
Sang Oh Kang ◽  
Kyung Hyun Min ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Multivariable Logistic Regression Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Final Model ◽  
Asian Populations ◽  
Tnf Α

Abstract Background: Despite the improvement from the introduction of tumor necrosis factor inhibitors (TNFi) in the rheumatoid arthritis (RA), TNFi therapy fails for more than 30% or results in a partial response. Thus, we aimed to explore treatment marker by examining the association of single nucleotide polymorphisms (SNPs) with response to TNFi therapy.Method: Genes associated with RA or RA treatment were reviewed and fourteen SNPs with minor allele frequency ≥ 20% in the East Asian populations were selected and analyzed. Data were collected from 105 RA patients. Our primary endpoint was the disease activity score using 28-joint count after six months of treatment (DAS28-6month). The secondary outcomes were the subcomponents of DAS28.Results: A total of 88 patients were included in the final analyses. Among the 14 SNPs analyzed, one SNP showed statistical significance in DAS28-6month: patients with the GG allele of RETN rs1862513 had a 4.7 times higher chance of low disease activity at 6-months than GC or CC-carriers (p = 0.033), as indicated by multivariable logistic regression analysis. Rs3397 was marginally significant in univariate analysis (p=0.059), but was significant in the multivariable model (p=0.041). The final model explained 24.5% (Nagelkerke R2) of the variance in DAS28-6month.Conclusion: Our results demonstrated that, among the genes related to RA, SNPs in RETN and TNFRSF1B were associated with the response of TNFi treatment.

scholarly journals Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents

2005 ◽  
Vol 35 (11) ◽  
pp. 1589-1598 ◽  
Author(s):  
HSIAO-FAN LIN ◽  
YU-LI LIU ◽  
CHIH-MIN LIU ◽  
SHUEN-IU HUNG ◽  
HAI-GWO HWU ◽  
...  
Keyword(s):  
Susceptibility Gene ◽  
Single Locus ◽  
Nucleotide Polymorphisms ◽  
Exon 2 ◽  
Neuregulin 1 ◽  
Schizotypal Personality ◽  
Regression Test ◽  
Single Locus Analysis ◽  
Personality Features ◽  
Perceptual Aberration

Background. We test the hypothesis that the neuregulin 1 (NRG1) gene at chromosome 8p22-p12, which has been implicated as a susceptibility gene to schizophrenia, is associated with variations in schizotypal personality in non-clinical populations.Method. A randomly selected sample of 905 adolescents were assessed for their personality features using the Perceptual Aberration Scale (PAS) and the Schizotypal Personality Questionnaire (SPQ) and genotyped for three single nucleotide polymorphisms (SNP8NRG221533, rs3924999, and rs2954041) at the NRG1 gene. Relations between the three genetic variants and continuous schizotypal personality scores were evaluated using ANOVA for single-locus analyses and haplotype trend regression test for multi-locus analyses.Results. Single locus analysis showed that the A allele of rs3924999, a functional polymorphism in exon 2, had the largest effect size and exhibited a prominent allele–dose trend effect for the PAS score. Haplotype analyses using the haplotype trend regression test indicated that the A allele of rs3924999 was mainly responsible for the association with the PAS but not with the SPQ or its three factors, and the magnitude of significance was not strengthened by the combination of this allele with adjacent locus.Conclusions. Our study provides the first evidence for the association of NRG1 with schizotypal personality and indicates a possible role of NRG1 in the genetic etiology of schizophrenia through perceptual aberrations.

PADI4 polymorphism predisposes male smokers to rheumatoid arthritis

2010 ◽  
Vol 70 (3) ◽  
pp. 512-515 ◽  
Author(s):  
Yuta Kochi ◽  
Mohamed M Thabet ◽  
Akari Suzuki ◽  
Yukinori Okada ◽  
Nina A Daha ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Smoking Status ◽  
Arginine Deiminase ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Logistic Regression Models ◽  
Environmental Interactions ◽  
Never Smokers ◽  
European Populations

ObjectiveTo elucidate the differential role of peptidyl arginine deiminase 4 (PADI4) polymorphism in rheumatoid arthritis (RA) between Asian and European populations, possible gene–environmental interactions among the PADI4 polymorphism, sex and smoking status were analysed.MethodsThree independent sets of case–control samples were genotyped for single-nucleotide polymorphisms in PADI4; Japanese samples (first set, 1019 RA patients, 907 controls; second set, 999 RA patients, 1128 controls) using TaqMan assays and Dutch samples (635 RA patients, 391 controls) using Sequenom MassARRAY platform. The association of PADI4 with RA susceptibility was evaluated by smoking status and sex in contingency tables and logistic regression models.ResultsIn the first set of Japanese samples, PADI4 polymorphism (rs1748033) showed a greater risk in men (ORallele 1.39; 95% CI 1.10 to 1.76; ptrend=0.0054) than in women and in ever-smokers (ORallele 1.25; 95% CI 1.02 to 1.53; ptrend=0.032) than in never-smokers. Moreover, the highest risk was seen in male ever-smokers (ORallele 1.46; 95% CI 1.12 to 1.90; ptrend=0.0047). Similar trends were observed in the second set of Japanese samples as well as in Dutch samples.ConclusionPADI4 polymorphism highly predisposes male smokers to RA, and the genetic heterogeneity observed between Asian and European populations may be partly explained by differences in smoking prevalence among men.

scholarly journals Association Between STAT4 rs7574865 Polymorphism and Rheumatoid Arthritis: Debate Unresolved

2018 ◽  
Vol 12 (1) ◽  
pp. 172-178
Author(s):  
Iman Tarakji ◽  
Wafa Habbal ◽  
Fawza Monem
Keyword(s):  
Rheumatoid Arthritis ◽  
Genetic Factors ◽  
Shared Epitope ◽  
Direct Sequencing ◽  
Healthy Controls ◽  
Asian Populations ◽  
Genotype Frequencies ◽  
Potential Impact ◽  
Acpa Status ◽  
Citrullinated Protein

Background: STAT4 rs7574865 polymorphism has been evidently associated with susceptibility to Rheumatoid Arthritis (RA) in European and Eastern Asian populations, whereas studies in other countries reported otherwise. Objective: We investigated the distribution of STAT4 rs7574865 polymorphism in a group of Syrian RA patients. Methods: Eighty-one RA patients and forty healthy controls were enrolled and STAT4 rs7574865 was genotyped by direct sequencing. RA patients were stratified according to Anti-Citrullinated Protein Antibodies (ACPA) status for analysis. Results: Minor T allele frequencies were 30.4%, 16.7%, and 23.8% in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively. No significant differences in STAT4 rs7574865 allele/genotype frequencies were found between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05). Conclusion: STAT4 rs7574865 TT genotype showed a potential impact on ACPA positivity in Syrian RA patients. However, STAT4 rs7574865 effect on RA onset and severity is minor compared to other genetic factors such as HLA-DRB1 shared epitope alleles.

scholarly journals Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China

2019 ◽  
Vol 42 (1) ◽  
pp. E21-E30 ◽  
Author(s):  
Xianguo Fu ◽  
Jing Yang ◽  
Xiaoyang Wu ◽  
Qifang Lin ◽  
Yuli Zeng ◽  
...  
Keyword(s):  
Association Studies ◽  
Direct Sequencing ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Han Chinese ◽  
Small Sample ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Asian Populations

Background: The prevalence of migraines in the She population, a minority in China, is significantly higher than that in Han Chinese and other Asian populations. Two single nucleotide polymorphisms (SNPs) have been found to be associated with migraine susceptibility in the She population. Purpose: This study investigated four SNPs, identified in genome-wide association studies, within migraine-susceptible loci in Han Chinese for their association with migraine susceptibility in the She population. Methods: Two-hundred unrelated migraine patients and 200 healthy controls were recruited. The SNPs examined included rs2651899 (PRDM16 ), rs2274316 (MEF2D ), rs7577262 (TRPM8) and rs11172113 (LRP1). Genotyping of the SNPs was performed by allele-specific polymerase chain reaction and direct sequencing. Results: No significant differences between the participants with migraines and controls (participants without migraines) were demonstrated in genotypes, alleles and allele carriage frequencies for the four SNPs. A subgroup analysis found that migraine with aura had a lower frequency of C allele positivity in rs2651899 than in healthy controls (59.6% vs. 74.5%, respectively; P < 0.034). Univariate analyses indicated that no genotype of the four SNPs had a significant association with migraines. Males had a lower risk of migraines, and advanced age was a significant risk factor for migraines in females. Conclusion: The SNPs in four migraine susceptible loci in Han Chinese were not risk factors for migraines in a relatively small sample of the She population.

A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population

2008 ◽  
Vol 68 (3) ◽  
pp. 377-383 ◽  
Author(s):  
K Shimane ◽  
Y Kochi ◽  
R Yamada ◽  
Y Okada ◽  
A Suzuki ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Leukocyte ◽  
Promoter Polymorphism ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Leukocyte Antigen ◽  
Asian Populations ◽  
Increased Risk ◽  
Stratified Analysis ◽  
Japanese Subjects

Objectives:Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects.Methods:We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion–deletion polymorphism in the IRF5 gene. We performed 2 sets of case–control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays.Results:A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated.Conclusions:These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.

scholarly journals Association of Single Nucleotide Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Autoimmune Type 1 Diabetes in Tunisians

2010 ◽  
Vol 17 (9) ◽  
pp. 1473-1477 ◽  
Author(s):  
Jihen Benmansour ◽  
Mouna Stayoussef ◽  
Fayza A. Al-Jenaidi ◽  
Mansoor H. Rajab ◽  
Chiheb B. Rayana ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Regression Analysis ◽  
Costimulatory Molecule ◽  
Susceptibility Gene ◽  
Rflp Analysis ◽  
Positive Association ◽  
Gene Variants ◽  
Nucleotide Polymorphisms ◽  
Tunisian Patients

ABSTRACT In addition to HLA and insulin genes, the costimulatory molecule CTLA-4 gene is a confirmed type 1 diabetes (T1D) susceptibility gene. Previous studies investigated the association of CTLA-4 genetic variants with the risk of T1D, but with inconclusive findings. Here, we tested the contributions of common CTLA-4 gene variants to T1D susceptibility in Tunisian patients and control subjects. The study subjects comprised 228 T1D patients (47.8% females) and 193 unrelated healthy controls (45.6% females). Genotyping for CTLA-4 CT60A/G (rs3087243), +49A/G (rs231775), and −318C/T (rs5742909) was performed by PCR-restriction fragment length polymorphism (RFLP) analysis. The minor-allele frequencies (MAF) for the three CTLA-4 variants were significantly higher in T1D patients, and significantly higher frequencies of homozygous +49G/G and homozygous CT60G/G genotypes were seen in patients, which was confirmed by univariate regression analysis (taking the homozygous wild type as a reference). Of the eight possible three-locus CTLA-4 haplotypes (+49A/G, −318C/T, and CT60A/G) identified, multivariate regression analysis confirmed the positive association of ACG (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.26 to 2.94), GCG (OR, 2.40; 95% CI, 1.11 to 5.21), and GTA (OR, 4.67; 95% CI, 1.52 to 14.39) haplotypes with T1D, after confounding variables were adjusted for. Our results indicate that CTLA-4 gene variants are associated with increased T1D susceptibility in Tunisian patients, further supporting a central role for altered T-cell costimulation in T1D pathogenesis.

Macrophage polarization related gene variants to predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with bevacizumab (bev) in combination with FOLFIRI.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 621-621
Author(s):  
Yu Sunakawa ◽  
Sebastian Stintzing ◽  
Volker Heinemann ◽  
Fotios Loupakis ◽  
Chiara Cremolini ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Direct Sequencing ◽  
Macrophage Polarization ◽  
Negative Control ◽  
The Other ◽  
Nucleotide Polymorphisms ◽  
Mutant Type ◽  
Exon 2 ◽  
Multivariable Analyses ◽  
The Impact

621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angiogenesis, acceleration of tumor invasion, and suppression of immunosurveillance. CCL2 promotes the polarization into M2 whereas histidine-rich glycoprotein (HRG) redirects M2 to M1. We hypothesized that single nucleotide polymorphisms (SNPs) in CCL2 and HRG may predict clinical outcome in mCRC pts treated with anti-VEGF drug in combination with chemotherapy. Methods: This study enrolled 4 pts cohorts treated with antibody drug plus FOLFIRI in prospective trials, A: KRAS exon 2 wild-type (KRAS wt) pts (n=84), B: mutant-type pts (n=89) from FOLFIRI-arm of TRIBE trial (NCT00719797), C: bev-arm (n=295), D: cetuximab-arm (n=297), served as negative control arm, from KRAS wt pts of FIRE3 trial (NCT00433927). Functionally significant SNPs, CCL2 rs4586, HRG rs9898, and HRGrs2228243, were analyzed by PCR-based direct sequencing for associations with response rate (RR), progression-free survival (PFS), and overall survival (OS) by uni- and multivariable analyses. Results: The minor G allele of HRG rs2228243 was significantly associated with better PFS, but not RR and OS, than the A/A genotype in both uni- and multivariable analyses (10.8 vs 9.3 months. HR: 0.62, p=0.048; HR: 0.57, p=0.040, respectively) in the cohort B while it was not associated in the other KRAS wt cohorts. In the cohort C, the minor C allele of CCL2 rs4586 correlated with significantly shorter OS, but not RR and PFS, in both uni- and multivariable analyses (22.3 vs 28.4 months. HR: 1.61, p=0.003; HR: 1.63, p=0.004, respectively). No significant association of CCL2 rs4586 was seen in the other cohorts although pts with the C allele of CCL2rs4586 had a negative marginal significant association in PFS and a shorter OS than pts with the T/T genotype (22.0 vs 30.8 months) in the cohort A. Conclusions: Our study provides evidence that SNPs in CCL2 and HRG may serve as a predictive or prognostic marker in mCRC pts treated with bev plus FOLFIRI. Our results also suggest that the impact of the SNPs on outcome may differ according to KRAS status. Prospective validation of this study is warranted.

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