Association study of miR-146a,miR-149, miR-196a2, and miR-499 polymorphisms with venous thromboembolism in a Korean population

Journal of Thrombosis and Thrombolysis - Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in...     

IRAK2 is associated with susceptibility to rheumatoid arthritis

This study was performed to investigate the association of the single nucleotide polymorphisms of interleukin-1 receptor-associated kinase 2 (IRAK2) rs3844283 and rs708035 with rheumatoid arthritis (RA). IRAK2 rs3844283 and rs708035genotyping was determined by mutagenically separated PCR with specifically designed primers in a cohort of 222 (30 men, 192 women, mean age 49 years) adult RA patients and 224 matched controls. IRAK2 rs3844283 C allele was detected in 66% of RA patients and 74% of controls. The CC genotype was the most frequent genotype in both RA patients (45.5%) and the controls (56.3%). The G allele was found to be associated with RA susceptibility (OR = 1.47, 95% CI = 1.10–1.96, p = 0.008). The GG genotype was found to be associated with RA in the co-dominant and the dominant models (OR = 2.03, 95% CI = 1.08–3.81, p = 0.042 and OR = 1.54, 95% CI = 1.06–2.23, p = 0.023, respectively). IRAK2 rs708035 was found not to be in the Hardy-Weinberg equilibrium. The hyperfunctional IRAK2 rs708035 A allele was more frequent in RA patients than in controls (69.9 versus 62.2%, respectively, p = 0.015). Moreover, IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium and the GA haplotype was significantly more frequent in RA patients than in controls (p = 0.034). This study for the first time ever reports the association of IRAK2 rs3844283, IRAK2 rs708035, and the corresponding haplotypes with RA. Functional studies are recommended to elucidate the risk posed by the GA haplotype for the development of RA.     

Lack of association between interleukin 23 receptor gene polymorphisms and rheumatoid arthritis susceptibility

The recent discovery of interleukin 23 (IL-23), its receptor, and the underlying signal transduction pathway has improved our understanding of cellular immunity. Several studies suggest that IL-23 is an essential promoter of chronic joint inflammation. In this report, we assess the possible association of interleukin 23 receptor (IL23R) polymorphisms and haplotypes with rheumatoid arthritis (RA). The study was conducted on 1,204 RA patients and 979 healthy controls. Seven polymorphisms were selected from previous IBD reports. The seven SNPs (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032 and rs1495965) were genotyped using the TaqMan assay. Comparison of RA and control subjects revealed no statistically significant differences in the distribution of the IL23R genotypes and haplotypes. Our results clearly indicate that IL23R gene polymorphisms do not play a significant role in susceptibility to RA in the Korean population. Accordingly, we conclude that IL23R gene polymorphisms cannot be applied as an effective genetic marker for RA susceptibility.     

Lack of association between polymorphisms of thrombogenic genes and disease susceptibility in rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased mortality due to cardiovascular disease (CVD). Abnormalities in coagulation have been linked with CVD in general and RA population. The aim of our study is to determine whether particular single nucleotide polymorphisms thought to be involved in the regulation of coagulation are over-represented in patients with RA compared to controls. We compared the frequency of atherothrombotic polymorphisms (Factor V Leiden, fibrinogen G455A, prothrombin G20210A and plasminogen activator inhibitor 4G5G) in 322 RA patients [231 females, mean age 61.5 ± 12, median disease duration 10 years (IQR = 14)] with 441 local controls. No significant differences were observed in genotype or allele frequencies either between RA and controls or between the disease subgroups studied. Whereas these polymorphisms may be of importance at the level of individual patients, they are unlikely to be clinically important on a population basis.     

GSTT1, GSTM1 and GSTP1 polymorphisms and susceptibility to juvenile idiopathic arthritis

OBJECTIVE: In this study we have analyzed GSTM1, GSTT1 and GSTP1 polymorphisms in patients with juvenile idiopathic arthritis (JIA), to investigate a possible role of these genes as genetic components of the disease. METHODS: A total of 103 individuals (49 oligoarticular, 41 polyarticular and 13 systemic) were analyzed for the three polymorphisms, using a PCR/RFLP methodology. RESULTS: We have observed significantly increased frequencies of individuals with GSTT1 null genotype in JIA patients comparing to controls (37% x 21%; p=0.0183). There was a 2-fold increased risk (OR 2.2, 95% CI 1.2-4.1) associating the disease with the GSTT1 null genotype. Considering the subgroups (oligoarticular, polyarticular and systemic), the results indicated an association between polyarticular and systemic patients and the GSTT1 null genotype. There was a 2-fold increased risk for polyarticular patients (OR 2.4, 95%, CI 1.1-5.4), and a 4-fold increased risk for systemic patients (OR 4.4, 95%, 1.3-14.5). CONCLUSION: The GSTT1 null genotype seems to be involved in polyarticular and systemic JIA.     

Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity

OBJECTIVE: To determine whether functional cytokine gene polymorphisms influence disease susceptibility and phenotype in patients with psoriatic arthritis (PsA). METHODS: DNA was obtained from 147 PsA patients and 389 controls. Seven functional proinflammatory (interleukin-1beta [IL-1beta] +3953, IL-6 -174, tumor necrosis factor alpha [TNFalpha] -308, TNFbeta +252) and antiinflammatory (IL-10 -1082, IL-10 -592, IL-1 receptor antagonist [intron 2, 86 bp, variable-number tandem repeat]) gene polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism assays. RESULTS: No significant difference in genotype frequencies was observed between the control and the PsA patient populations, and no association with Steinbrocker functional class, disease classification (polyarticular or oligoarticular), presence of spinal involvement, or age at PsA onset was observed. The presence of joint erosions was significantly associated with the TNFalpha -308 and TNFbeta +252 polymorphisms (P < 0.0001 and P = 0.0017, respectively). Frequencies of the TNFalpha -308 and TNFbeta +252 genotypes were also significantly different (P = 0.0078 and P = 0.0486, respectively) in a group of progressors (patients with early PsA in whom the number of joint erosions in the hands and feet increased over a median interval of 24 months) compared with a group of nonprogressors. Age at psoriasis onset was significantly associated with the TNFbeta +252 and TNFalpha -308 polymorphisms (P = 0.0003 and P = 0.0081, respectively). The TNFB2B2 and TNFalpha -308 AA genotypes were associated with the earliest mean ages at psoriasis onset. CONCLUSION: The TNFalpha -308 and TNFbeta +252 polymorphisms were significantly associated with age at psoriasis onset, presence of joint erosions in PsA, and progression of joint erosions in early PsA. TNF gene polymorphisms may be useful prognostic markers in PsA, and these results support the rationale for using anti-TNF treatment in patients with severe, progressive PsA.     

微小RNA-146a对类风湿关节炎患者滑膜成纤维细胞抑制作用的研究

目的 研究微小RNA-146a(miR-146a)对类风湿关节炎(RA)患者滑膜成纤维细胞增殖及细胞因子分泌的影响.方法 体外分离培养RA患者滑膜成纤维细胞,脂质体转染化学合成的miR-146a,~3H掺入法检测滑膜成纤维细胞增殖.酶联免疫吸附试验(ELISA)法检测细胞上清白细胞介素(IL)-8及IL-6水平.实时定量聚合酶链反应(PCR)检测滑膜成纤维细胞中miR-146a靶分子肿瘤坏死因子受体相关因子6(TRAF6)、IL-受体相关激酶(IRAKI)的mRNA水平.应用独立样本t检验进行统计学分析.结果 与阴性对照小RNA相比,miR-146a转染后的滑膜成纤维细胞增殖能力明显下降(2015±545与8799±1922,P<0.01),IL-8及IL-6分泌受到明显抑制[(153±49)pg/ml与(311±123)pg/ml,P<0.01和(295±95)pg/ml与(459±126)pg/ml,P<0.05].定量PCR检测IRAK1的mRNA水平显示,miR-146a转染可明显下调滑膜成纤维细胞IRAK1的表达(0.28±0.07与1,P<0.01).结论 miR-146a可能通过下调IRAKI表达,进而抑制滑膜成纤维细胞增殖及IL-8、IL-6等炎性细胞因子分泌,从而发挥抑制RA滑膜炎症的作用.     

Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis and meta-regression

This study aimed to explore whether interleukin-10 polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). Studies that have analyzed the associations of the interleukin-10-1082G>A, -592C>A, and -819C>T polymorphisms with RA were searched for in PubMed and EMBASE. Sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Egger’s linear regression and Begg’s funnel plots were performed to analyze publication bias. The source of heterogeneity was analyzed by subgroup analysis and meta-regression. This meta-analysis involved 2661 RA patients and 3249 controls in 16 studies. There were significant associations with RA in the AG vs AA model (OR?=?0.79, 95% CI?=?0.67–0.93, P?<?0.01) and the AG + GG vs AA model (OR?=?0.80, 95% CI?=?0.69–0.93, P?<?0.01) for the interleukin-10-1082G>A polymorphism, in the TC vs TT model (OR?=?0.61, 95% CI?=?0.44–0.84, P?<?0.01) and the CC vs TT model (OR?=?0.64, 95% CI?=?0.46–0.89, P?<?0.01) for the interleukin-10-819C>T polymorphism, and in the AC vs AA model (OR?=?0.73, 95% CI?=?0.56–0.96, P?=?0.03) and the AC + CC vs AA model (OR?=?0.68, 95% CI?=?0.47–0.98, P?=?0.04) for the interleukin-10-592C>A polymorphism. Meta-regression revealed that the genotyping method was a major cause of heterogeneity in the AC vs AA model and the AC + CC vs AA model for the interleukin-10-592C>A polymorphism. This meta-analysis showed the interleukin-10-1082G>A, -592C>A, and -819C>T polymorphisms are correlated with the susceptibility to RA. Meta-regression indicated that the genotyping method is a major driver of heterogeneity in the relationship between the interleukin-10-592C>A polymorphism and RA.     

谷胱甘肽S-转移酶M1、T1基因多态与散发性大肠腺癌遗传易感性

目的　探讨谷胱甘肽S 转移酶 (GST)M1、T1基因多态与散发性大肠腺癌 (SCRAC)遗传易感性的关联。方法　应用多重聚合酶链反应 (PCR)技术 ,对经病理组织学确诊的 10 4例SCRAC患者及同期在本院体检的无血缘关系的 10 1例健康人 ,检测其GSTM1和GSTT1基因多态性。结果　 (1)在健康人和SCRAC患者 ,GSTM1、GSTT1空白基因型的频率差异均无显著性 (前者 4 6 5 % :5 6 7% ,χ2 =2 13,P >0 0 5 ;后者 4 7 5 % :6 0 6 % ,χ2 =3 5 2 ,P >0 0 5 )。 (2 )GSTM1空白基因型频率在近端与远端SCRAC患者间、在老年与非老年SCRAC间的频率差异均无显著性 ;而GSTT1空白基因型的频率差异有显著性 (前者 4 4 4 % :6 6 2 % ,χ2 =3 97,P <0 0 5 ;后者 70 9% :4 9 0 % ,χ2 =5 2 1,P <0 0 5 )。 (3)GSTM1、GSTT1均为空白基因联合型的个体患SCRAC的危险性升高 4 33倍 (9 6 % :2 6 9% ,χ2 =7 89,ν =3,P <0 0 5 )。结论　单独的GSTM1或GSTT1空白基因型与SCRAC遗传易感性无关 ,但GSTT1空白基因型与远端SCRAC遗传易感性有关 ,且多见于老年患者。GSTM1、GSTT1均为空白基因的联合基因型是SCRAC的易感基因型。     

VEGF gene polymorphisms and susceptibility to rheumatoid arthritis

OBJECTIVES: To investigate polymorphisms of the VEGF gene in patients with rheumatoid arthritis (RA), their relationship to clinical features and the radiographic progression of joint disease. METHODS: One hundred and forty patients with RA and 149 healthy unrelated controls were recruited. We examined four polymorphisms of the VEGF gene which are reported to be associated with production of vascular endothelial growth factor (VEGF), using polymerase chain reaction (PCR) restriction fragment length polymorphism assay and amplification refractory mutation system (ARMS) PCR. Haplotypes were predicted by Bayesian algorithm using the Phase program. RESULTS: All four polymorphisms were in Hardy-Weinberg equilibrium in both patients and controls. The frequency of the 936 T allele, which has been associated with lower production of VEGF, was significantly increased in RA patients compared with controls (22.7 vs 13.4%, P = 0.002). The frequencies of two haplotypes (CGCT and AAGT) which were predicted using the Phase program were significantly increased in RA patients compared with controls [33 vs 14%, odds ratio (OR) 2.636, 95% confidence interval (CI) 1.38-5.04 for CGCT; 17 vs 6%, OR 3.08, 95% CI 1.20-7.92 for AAGT]. The carriers of the susceptible haplotypes in RA patients had a younger age at disease onset but did not show a difference in the progression rate of radiographic joint destruction. CONCLUSIONS: Our data suggest that the VEGF gene may play a role in the development of RA     

PADI4 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis

The objective of the study was to investigate the association between peptidylarginine deiminase 4 (PADI4) polymorphism and susceptibility to rheumatoid arthritis (RA). An electronic searching strategy was employed to collect relevant studies on the association between PADI4 polymorphism and susceptibility to RA. The odds ratio (OR) with the 95 % confidence interval (95 % CI) was used to evaluate the RA risk presented by PADI4 polymorphism. Fixed or random effects models were selected based on heterogeneity. Publication bias was assessed using funnel plots, Begg’s test, and Egger’s test. A total of 27 studies from 21 articles were included. Six gene loci (padi4_94, 104, 92, 90, 89, and 100) were chosen for the meta-analysis. The pooled ORs (95 % CI) for allele 2 versus 1 were 1.08 (1.05–1.12), 1.17 (1.12–1.23), 1.26 (1.18–1.36), 1.17 (1.10–1.24), 1.30 (1.17–1.44), and 1.25 (1.11–1.40), respectively. All six SNPs were significantly associated with RA in Asian populations. Three SNPs (PADI4_104, 90, 89) showed significant associations, while the other three SNPs (PADI4_94, 92, 100) exhibited no associations in the European population. A dose–response relationship between allele 2 of PADI4 and the risk of RA was also identified. In conclusion, this meta-analysis suggests that PADI4 polymorphisms represent a significant risk factor for RA, especially in Asians.     

PARP-1基因多态性与胃癌易感性的关系

目的:探讨聚腺苷二磷酸核糖聚合酶-1(PARP-1)Val762Ala,Lys940Arg基因多态性与甘肃省地区汉族人群胃癌易感性的关系.方法:采用多重单碱基延伸SNP分型技术(Multiplex SNaPshot)对甘肃省胃癌高发区河西地区汉族人群中经病理确诊的原发性胃癌150例,健康对照组152例进行PARP-1基因2个SNP位点基因分型.使用ELISA法检测H.pylori感染.结果:发现PARP.1 940Lys/Arg基因型分布在胃癌组明显高于对照组(OR=2.917,95%CI:1.430-5.947.P=0.002);PARP-1762 Val/Ala基因型分布在胃癌组明显高于对照组(OR=1.685.95%CI:1.040-2.729,P=0.034).分层分析显示,在吸烟人群中,PARP-1 940Lys/Arg基因型携带者患胃癌的风险是Lys/Lys型携带者的8.430倍(OR=8.340;95%CI:2.664-26.144,P=0.000);在饮酒人群中,PARP-1 940Lys/Arg基因型携带者患胃癌的风险是Lys/Lys型携带者的3.333倍(OR=3.333,95%CI:1.214-9.155,P=0.015),在H.pylori感染阳性人群中,PARP-1 762A1a/Ala基因型携带者患胃癌的风险是Val/Val携带者的2.360倍(OR=2.360.95%CI:1.256-4.433,P=0.007).同时携带PARP-1 940 Lys/Arg和PARP-1 762Ala/Ala+Val/Ala基因型的个体患胃癌的发病风险是PARP-1 940Lys/Lys和PARP-1 762Val/Val基因型携带者的4.2倍(OR=4.200,95%CI:1.430-12.338.P=0.006).结论:PARP-1 940Lys/Arg和PARP-1 762Ala/Ala或Ala/Ala基因型与中国甘肃地区汉族人群胃癌发病风险增高相关;PARP-1 Lys940Arg 与吸烟,饮酒,PARP-1 Val762Ala与H.pylori感染以及PARP-1 Lys940Arg与PARP-1 Val762Ala在胃癌的发病风险中都各自存在着加乘交互效应.     

The association between seven ERAP1 polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis involving 8,530 cases and 12,449 controls

Besides the MHC gene, HLA-B27, ERAP1 is one of the non-MHC genes which also play key roles in the pathogenesis of AS. It has been reported that there is an association between ERAP1 polymorphisms and AS Risk. However, the results were inconclusive. The aim of the current study was to determine the contribution of ERAP1 polymorphisms to ankylosing spondylitis (AS) susceptibility. To derive a more precise estimation of the association, a meta-analysis was performed by searching the MEDLINE and EMBASE data base. The crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to access the strength of association between ERAP1 polymorphisms and AS risk. The pooled ORs were performed for minor allele versus major allele in all polymorphisms. Nine case–control studies consisting of 8,530 AS patients and 12,449 controls were identified in this meta-analysis. Except in rs27434 (P = 0.23), the significant correlation between ERAP1 polymorphisms and AS susceptibility has been detected in rs27044 (OR 1.57, P < 0.001), rs17482078 (OR 1.271, P < 0.001), rs10050860 (OR 0.772, P = 0.006), rs30187 (OR 1.348, P < 0.001), rs2287987 (OR 0.746, P < 0.001) and rs27037 (OR 1.257, P = 0.001). This meta-analysis demonstrates that the ERAP1 polymorphisms may play a significant role in susceptibility to AS. However, this result should be identified by more convincing experimental evidences in molecular level and population level.     

Neuroendocrine gene polymorphisms and susceptibility to juvenile idiopathic arthritis

OBJECTIVE: To investigate the involvement of neuroendocrine candidate genes in the aetiopathogenesis of juvenile idiopathic arthritis (JIA). METHODS: Single-nucleotide polymorphisms and intragenic microsatellite markers within five neuroendocrine candidate genes (CRH, CBG, CYP19, ESR1, PRL) were investigated in 463 clinically characterized UK Caucasian JIA patients and a panel of 276 unrelated, healthy UK Caucasian controls. RESULTS: None of the polymorphisms investigated showed any statistically significant associations with JIA. CONCLUSIONS: The lack of association with polymorphisms of these neuroendocrine genes suggests that they are not involved in susceptibility to JIA.     

Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis

Objective

To investigate the involvement of candidate cytokine genes in the pathogenesis of juvenile idiopathic arthritis (JIA).

Methods

Single nucleotide polymorphisms and intragenic microsatellite markers within 8 candidate cytokine genes (interleukin‐1α [IL‐1α], IL‐2, IL‐4, IL‐6, IL‐10, interferon‐α1 [IFNA1], interferon‐γ [IFNG], and interferon regulatory factor 1 [IRF‐1]) were investigated in 417 Caucasian patients with clinically characterized JIA and a panel of 276 unrelated, healthy Caucasian controls, all from the United Kingdom.

Results

A novel 3′–untranslated region (3′UTR) polymorphism in IRF‐1 was found to be associated with susceptibility to JIA (corrected P = 0.002). No significant association with IL‐1α, IL‐2, IL‐4, IL‐6, IL‐10, IFNA1, or IFNG was observed.

Conclusion

An association between JIA and a previously unreported 3′UTR polymorphism of IRF‐1 was observed. This association was not found to be specific to any particular JIA subgroup. This suggests that IRF‐1 may contribute to a common pathogenesis shared by all JIA patients, regardless of clinical phenotype. This is most likely to be a genetic contribution to the chronic inflammatory process that underlies JIA pathology.