Association ofEMCNwith Susceptibility to Rheumatoid Arthritis in a Japanese Population

2010 ◽  
Vol 38 (2) ◽  
pp. 221-228 ◽  
Author(s):  
KAZUMASA NISHIMOTO ◽  
KATSUNORI IKARI ◽  
HIROTAKA KANEKO ◽  
SO TSUKAHARA ◽  
YUTA KOCHI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Functional Study ◽  
Positive Staining ◽  
Nucleotide Polymorphisms ◽  
Data Set ◽  
Nuclear Factors ◽  
Validation Set ◽  
Synovial Tissues ◽  
Stratified Analysis

Objective.Endomucin, an endothelial-specific sialomucin, is thought to facilitate “lymphocyte homing” to synovial tissues, resulting in the major histopathologies of rheumatoid arthritis (RA). We examined the association between RA susceptibility and the gene coding endomucin,EMCN.Methods.Association studies were conducted with 2 DNA sample sets (initial set of 1504 patients, 752 controls; and validation set, 1113 patients, 940 controls) using 6 tag single-nucleotide polymorphisms (SNP) from the Japanese HapMap database. Immunohistochemistry for the expression of endomucin was conducted with synovial tissues from 4 patients with RA during total knee arthroplasty. Electromobility shift assays were performed for the functional study of identified polymorphisms.Results.Within the initial sample set, the strongest evidence of an association with RA susceptibility was SNP rs3775369 (OR 1.20, p = 0.0075). While the subsequent replication study did not initially confirm the observed significant association (OR 1.13, p = 0.062), an in-depth stratified analysis revealed significant association in patients testing positive to anti-cyclic citrullinated peptide (anti-CCP) antibody in the replication data set (OR 1.15, p = 0.044). Investigating 2 sample sets, significant associations were detected in overall and stratified samples with anti-CCP antibody status (OR 1.17, p = 0.0015). Positive staining for endomucin was detected in all patients. The allele associated with RA susceptibility had a higher binding affinity for HEK298-derived nuclear factors compared to the nonsusceptible allelic variant of rs3775369.Conclusion.A significant association betweenEMCNand RA susceptibility was detected in our Japanese study population. TheEMCNallele conferring RA susceptibility may also contribute to the pathogenesis of RA.

scholarly journals Linkage and Association Studies of Joint Morbidity from Rheumatoid Arthritis

2009 ◽  
Vol 37 (2) ◽  
pp. 291-295 ◽  
Author(s):  
JIN-YOUNG MIN ◽  
KYOUNG-BOK MIN ◽  
JOOHON SUNG ◽  
SUNG-IL CHO
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Clinical Signs ◽  
Joint Damage ◽  
Genetic Variations ◽  
Nucleotide Polymorphisms ◽  
Sibling Pairs ◽  
Rf Values ◽  
Family Based ◽  
The Relationship

Objective. To investigate the relationship between genetic variations of rheumatoid arthritis (RA) susceptibility in terms of joint morbidity.Methods. We used data from Genetic Analysis Workshop 15. The Illumina linkage panel IV included 5858 single-nucleotide polymorphisms (SNP), with 5744 SNP passing quality control filters. The phenotypic variables analyzed were the level of rheumatoid factor (RF) and score on the Joint Alignment and Motion (JAM) scale. We modified the scale, dividing by RF values relevant to disease severity. Linkage analysis for affected sibling pairs was done using the MERLIN program, and family-based association tests were carried out using PLINK and FBAT software.Results. We found a high peak (LOD = 3.29; NPL Z = 4.07) near the HLA-DRB1 region on chromosome 6. The linkage at 6p24 at rs1410766 [LOD = 2.66; nonparametric linkage (NPL) Z = 3.23] was statistically significant. Two other regions also showed possible linkage peaks: chromosome 7q30 at rs322812 (LOD = 2.47; NPL Z = 3.39) and chromosome 15p34 at rs347117 (LOD = 1.95; NPL Z = 2.80). For the family-based association study, 7 SNP related to clinical RA severity were detected.Conclusion. Genetic variations may lead to an enhanced risk of joint damage and increased levels of RF. Further studies are needed to elucidate the roles of other genes involved in RA and to explore whether the clinical signs of RA are associated with particular genetic variations.

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.

Genetics of rheumatoid arthritis

2013 ◽  
Author(s):  
Steve Eyre ◽  
Jane Worthington
Keyword(s):  
Rheumatoid Arthritis ◽  
Large Scale ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Convincing Evidence ◽  
Susceptibility Locus ◽  
Small Scale ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hla Association

A range of epidemiological studies have clearly established that susceptibility to rheumatoid arthritis (RA) is determined by both genetic and environmental factors. Studies over the last five decades have used a variety of approaches to identify the genetic variants associated with disease. HLA DRB1 was the first RA susceptibility locus to be discovered and has the largest effect size. We describe current understanding of the complexities of HLA association for RA. Linkage and small-scale association studies prior to 2007 provided convincing evidence for only one more RA susceptibility locus, PTPN22. Major breakthroughs in high-throughput genotyping and systematic discovery and mapping of hundreds of thousands of single nucleotide polymorphisms (SNPs) led to large-scale genome-wide association studies used for the first time for RA in 2007. This approach has had a dramatic impact on our knowledge of the susceptibility loci for RA, such that over 60 risk variants have now been robustly identified. We present an overview of these studies and the loci that have been identified. We consider how this knowledge is contributing to a greater understanding of the aetiology and pathology of the disease and in turn how this can influence management of patients presenting with an inflammatory arthritis. We consider some of the unanswered questions and the approaches that will need to be taken to address them.

Association between ADAMTS7 TagSNPs and the risk of myocardialinfarction

2019 ◽  
Vol 95 (1127) ◽  
pp. 487-492
Author(s):  
Li-li Liang ◽  
Yu-lan Zhou ◽  
Jie Cheng ◽  
Yu-tong Xiao ◽  
Zi-bin Tang ◽  
...  
Keyword(s):  
Association Studies ◽  
Multivariate Logistic Regression Analysis ◽  
Underlying Mechanism ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
General Validity ◽  
Genome Wide ◽  
Increased Risk ◽  
Stratified Analysis

Purpose of the studyGenome-wide association studies have revealed an association of ADAMTS7 polymorphisms with the risk of cardiovascular diseases. Nonetheless, the role of ADAMTS7 polymorphisms on myocardial infarction (MI) risk remains poorly understood. Here, we aim to evaluate the effect of ADAMTS7 tag single nucleotide polymorphisms (SNPs) on individual susceptibility to MI.Study designGenotyping of the four tagSNPs (rs1994016, rs3825807, rs4380028 and rs7173743) was performed in 232 MI cases and 661 control subjects using PCR-ligase detection reaction (LDR) method. The association of these four tagSNPs with MI risk was performed with SPSS software.ResultsMultivariate logistic regression analysis showed that ADAMTS7 tagSNP rs3825807 exhibited a significant effect on MI risk. Compared with the TT homozygotes, the CT genotype (OR1.93, 95% CI1.30to 2.85, Pc=0.004) and the combined CC/CT genotypes (OR1.70, 95% CI1.16 to 2.50, Pc=0.028) were statistically significantly associated with the increased risk for MI. Further stratified analysis revealed a more significant association with MI risk among older subjects, hypertensives, non-diabetics and patients with hyperlipidaemia. Consistently, the haplotype rs1994016T–rs3825807C containing rs3825807 C allele exhibited increased MI risk (OR1.52, 95% CI1.10 to 2.10, p=0.010). However, we did not detect any association of the other three tagSNPs with MI risk.ConclusionsOur finding suggest that ADAMTS7 tagSNP rs3825807 contributes to MI susceptibility in the Chinese Han population. Further studies are necessary to confirm the general validity of our findings and to clarify the underlying mechanism for this association.

scholarly journals Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

2009 ◽  
Vol 69 (6) ◽  
pp. 1049-1053 ◽  
Author(s):  
Anne Hinks ◽  
Steve Eyre ◽  
Xiayi Ke ◽  
Anne Barton ◽  
Paul Martin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Disease ◽  
Disease Susceptibility ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Susceptibility Loci ◽  
Genotype Frequencies ◽  
Published Evidence

BackgroundGenome-wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of using information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association with two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features with JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci.ObjectiveTo determine the overlap of disease susceptibility loci for RA and JIA.MethodsFifteen single nucleotide polymorphisms (SNPs) at nine RA-associated loci were genotyped in Caucasian patients with JIA (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK.ResultsTwo JIA susceptibility loci were identified, one of which was a novel JIA association (STAT4) and the second confirmed previously published associations of the TRAF1/C5 locus with JIA. Weak evidence of association of JIA with three additional loci (Chr6q23, KIF5A and PRKCQ) was also obtained, which warrants further investigation.ConclusionAll these loci are good candidates in view of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T-cell receptor signalling or activation pathways.

scholarly journals Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis

2008 ◽  
Vol 68 (9) ◽  
pp. 1494-1497 ◽  
Author(s):  
I Marinou ◽  
K Walters ◽  
M C Dickson ◽  
M H Binks ◽  
D E Bax ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Risk ◽  
Single Gene ◽  
Interleukin 1 ◽  
Nucleotide Polymorphisms ◽  
Gene Effects ◽  
Single Nucleotide ◽  
Selenoprotein S ◽  
Stratified Analysis ◽  
Necrosis Factor

Objective:Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1β and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF.Methods:Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel–Haenszel (M–H) test and the linkage disequilibrium (LD)-based statistic.Results:No association of SELS −105 genotype and RA susceptibility was detected. Stratification of SELS −105 genotypes by IL1 −511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS −105 locus) in individuals with the GG/AG genotype at the IL1β −511 locus was significantly lower than that in individuals having the AA genotype at the IL1β −511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M–H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS −105 and IL6 or TNF variants.Conclusion:Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene–gene interactions in the pathogenesis of RA.

Genetics of rheumatoid arthritis

2013 ◽  
pp. 308-312
Author(s):  
Steve Eyre ◽  
Gisela Orozco ◽  
Jane Worthington
Keyword(s):  
Rheumatoid Arthritis ◽  
Large Scale ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Convincing Evidence ◽  
Susceptibility Locus ◽  
Small Scale ◽  
Nucleotide Polymorphisms ◽  
Risk Variants ◽  
Genetic And Environmental Factors

A range of epidemiological studies have clearly established that susceptibility to rheumatoid arthritis (RA) is determined by both genetic and environmental factors. Studies over the last five decades have used a variety of approaches to identify the genetic variants associated with disease. HLA-DRB1 was the first RA susceptibility locus to be discovered and has the largest effect size. We describe current understanding of the complexities of HLA association for RA. Linkage and small-scale association studies prior to 2007 provided convincing evidence for only one more RA susceptibility locus, PTPN22. Major breakthroughs in high-throughput genotyping, and systematic discovery and mapping of hundreds of thousands of single nucleotide polymorphisms (SNPs) led to large-scale genome-wide association studies used for the first time for RA in 2007. Widespread utilization of this approach has had a dramatic impact on our knowledge of the susceptibility loci for RA, such that over 100 risk variants have now been robustly identified. We present an overview of these studies and the loci that have been identified. We consider how this knowledge is contributing to a greater understanding of the aetiology and pathology of the disease, and in turn how this can influence management of patients presenting with an inflammatory arthritis. We consider some of the unanswered questions and the approaches that will need to be taken to address them.

Genetics of rheumatoid arthritis

2016 ◽  
Author(s):  
Steve Eyre ◽  
Jane Worthington ◽  
Sebastien Viatte
Keyword(s):  
Rheumatoid Arthritis ◽  
Large Scale ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Convincing Evidence ◽  
Susceptibility Locus ◽  
Small Scale ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hla Association

A range of epidemiological studies have clearly established that susceptibility to rheumatoid arthritis (RA) is determined by both genetic and environmental factors. Studies over the last five decades have used a variety of approaches to identify the genetic variants associated with disease. HLA DRB1 was the first RA susceptibility locus to be discovered and has the largest effect size. We describe current understanding of the complexities of HLA association for RA. Linkage and small-scale association studies prior to 2007 provided convincing evidence for only one more RA susceptibility locus, PTPN22. Major breakthroughs in high-throughput genotyping, and systematic discovery and mapping of hundreds of thousands of single nucleotide polymorphisms (SNPs) led to large-scale genome-wide association studies used for the first time for RA in 2007. Widespread utilization of this approach has had a dramatic impact on our knowledge of the susceptibility loci for RA, such that over 100 risk variants have now been robustly identified. We present an overview of these studies and the loci that have been identified. We consider how this knowledge is contributing to a greater understanding of the aetiology and pathology of the disease, and in turn how this can influence management of patients presenting with an inflammatory arthritis. We consider some of the unanswered questions and the approaches that will need to be taken to address them.

Causal relationship between years of education and the occurrence of rheumatoid arthritis

2019 ◽  
Vol 95 (1125) ◽  
pp. 378-381 ◽  
Author(s):  
Sang-Cheol Bae ◽  
Young Ho Lee
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Causative Relationship ◽  
Weighted Median ◽  
The Uk ◽  
Education And Development

ObjectiveTo search out whether or not years of education is causally related to rheumatoid arthritis (RA).MethodWe conducted a two-sample Mendelian randomisation (MR) analysis employing inverse-variance weighted (IVW), weighted median and MR-Egger regression analysis. We chose statistic data of years of education from the UK Biobank genome-wide association studies (GWASs) (n=293 723) as the exposure and a meta-analysis of GWASs of RA with autoantibody (n=5539) and European controls (n=20 169) as the outcome.ResultsWe selected a total of 49 single nucleotide polymorphisms as instrumental variables (IVs). The IVW method instructed an inverse causative relationship between years of education and RA (β=− 0.039, SE=0.283, p=0.008). MR-Egger regression test showed that directional pleiotropy seems not to bias the MR results (intercept=0.028; p=0.358). MR-Egger analysis demonstrated no causative relationship between RA and years of education (β=− 2.320, SE=1.709, p=0.181). However, the weighted median approach indicated a causative association between RA and years of education (β=−0.950, SE=0.355, p=0.008).ConclusionsThe MR analysis supported a potential inverse causative relationship between years of education and development of RA.

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