类风湿关节炎易感基因多态性研究进展

类风湿关节炎(rheumatoid arthritis,RA)是一种常见于中青年人群的自身免疫性疾病。有研究报道,该病发病呈逐年升高态势,并且会给患者、家庭与社会带来严重后果,因而对RA的早期诊断、治疗和预防十分重要。目前研究虽然对该病发病机制暂不是十分明了,但随着分子技术的发展以及对该病研究的逐渐深入,对其发病有了更加深入的了解。近年来诸多资料表明,某些基因多态性位点很可能增加了RA的易感性,且与疾病的病理生理进展及预后判断具有显著相关性。因此了解RA与相关基因多态性的关系,将会对该病发生机制有更深入的理解,并为今后临床治疗RA提供根据。本文总结了目前有关RA易感性与相关基因多态性的研究进展,并作如下综述。     

几种基因的单核苷酸多态性与类风湿关节炎

单核苷酸多态性(SNPs)是新一代的基因分子标记,随着人类基因组图谱的绘制成功,SNPs被应用于寻找各种致病基因。类风湿关节炎(RA)是一种全身自身免疫性疾病,到目前为止,其发病机制尚未完全清楚。本文简要介绍了SNPs及几种基因的SNPs与RA的关系。     

TBX21基因多态性与类风湿关节炎相关性的研究

目的:研究TBX21基因单核苷酸多态性(SNPs)与中国汉族人群类风湿性关节炎(RA)的关系。方法:采用单碱基延伸法(SBE)检测288例RA患者和288名正常健康者TBX21基因的5个SNPs:rs4794067、rs2240017、rs17250932、rs2074190和rs12721470的基因型。结果:5个SNP位点的基因型均符合Hardy-Weinberg平衡(P0.05)。rs12721470位点的基因型频率和等位基因频率在RA组和对照组间的差别具有统计学意义。rs4794067位点的基因型频率在RA组和对照组间无统计学差异,而等位基因频率在RA组和对照组间的差异则具有统计学意义(P0.05)。rs17250932、rs2240017和rs2074190基因型及等位基因频率在RA组和对照组间无统计学意义(P0.05)。结论:TBX21基因单核酸多态性rs12721470与中国汉人群类风湿关节炎是显著相关联的。     

白介素受体相关激酶-1基因多态性与类风湿关节炎的相关性

目的探讨白介素受体相关激酶-1(IRAK1)rs3027898和rs1059703多态性性与类风湿关节炎(RA)易感性及临床参数的关系。方法收集RA患者123例和体检的220名健康对照者外周血标本,采用聚合酶链反应-连接酶检测反应(PCR-LDR)方法检测IRAK1 rs3027898和rs1059703基因多态性,收集并计算RA患者临床参数:发病年龄、性别、RF抗体、抗CCP抗体、RA疾病活动(DAS28≥3.2)、骨破坏和用药情况。结果 RA组IRAK1 rs3027898和rs1059703的基因型频率和等位基因频率与健康对照组比较,差异无统计学意义(P>0.05)。RA患者IRAK1 rs3027898和rs1059703基因型与发病年龄、性别、RF抗体和抗CCP抗体阳性率、骨破坏阳性率均无相关性(P>0.05)。RA患者IRAK1 rs3027898基因型与RA疾病活动无相关性(P>0.05),RA患者IRAK1 rs1059703基因型与RA疾病活动存在相关性(P<0.05),携带CT+TT基因型RA患者疾病活动的风险是携带CC基因型RA患者4.243倍(P=0.023,OR=4.243,95%CI为1.223～14.715)。结论我国汉族人群中,IRAK1 rs3027898和rs1059703多态性与RA的易感性无关,但IRAK1 rs1059703多态性可能是RA患者疾病活动的一个遗传危险因素。     

IL-17在类风湿关节炎患者外周血表达的临床意义

目的：探讨IL-17在类风湿关节炎（ RA）发病中的作用及意义。方法：采用逆转录-聚合酶链反应（ RT-PCR）法检测66例RA患者（活动期34例、缓解期32例）和44例健康对照组外周血单个核细胞（ PBMC）中IL-17 mRNA 的表达水平,采用酶联免疫吸附试验（ ELISA）检测各组血清中IL-17的浓度,用免疫比浊法检测各组血清RF的浓度,分析血清IL-17与RF的相关性。结果：RA患者PBMC中IL-17 mRNA的表达显著高于健康对照组（ P＜0.05）,但活动期与缓解期无明显差异（ P＞0.05）;RA活动期患者血清IL-17水平显著高于RA缓解期患者和健康对照组（ P＜0.05）;且RA患者血清IL-17水平与RF呈正相关。结论：IL-17和RF在RA的发病和病理过程中起重要作用,IL-17可能与RA活动性有关。     

骨保护素基因单核苷酸多态性与类风湿关节炎发病的相关性研究

 目的：探讨骨保护素（OPG）基因163A/G及245T/G单核苷酸多态性（SNPs）与我国汉族人群类风湿关节炎（RA）发病的相关性。方法：采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测我国南方汉族正常人群及RA患者的OPG 163A/G 和245T/G 2个SNP位点;进行Hardy-Weinberg平衡检验;计算基因型和等位基因频率,及这2个位点的连锁关系,并分析这2个SNP位点与RA的关系。结果：所研究基因分布符合Hardy-Weinberg平衡,163A/G 位点基因型AA、AG、GG分布频率在2组比较有显著差异（P<0.05）;等位基因A、G分布比较在2组有显著差异（P<0.05）,携带163GG基因型者发生RA的危险性是非携带者的1.219倍（OR=1219, 95％CI：1066~2.339, P<0.05)。但245T/G位点各基因型及等位基因频率在2组中均未见差异（P>005）。结论：OPG 基因 163A/G SNP可能与我国汉族人群RA发病相关,携带G等位基因可能是发病的危险因素。     

IL-18基因多态性与系统性红斑狼疮相关性的Meta分析

目的评价IL-18基因多态性与系统性红斑狼疮(systemic lupus erythematosus,SLE)的关系。方法检索中国学术期刊全文数据库(CNKI)、万方数据库、中国生物医学文献数据库(CBM)、PubMed、Embase和Web of Knowledge数据库,检索时间范围为1997年01月01日至2012年07月01日。按照纳入和排除标准纳入合格文献,并对其进行质量评价,用Stata 11.0软件进行Meta分析。结果共纳入10篇文献,收集到2 646例病例,2 761例对照,Meta分析结果显示欧裔人群中的IL-18-1297C/T(OR=1.388,95%CI=1.242～1.551,P<0.001)和-607A/C(OR=1.158,95%CI=1.014～1.322,P=0.031)多态性与SLE有关,欧裔人群中IL-18-1297在显性模型下(CC+CT vs TT)和隐性模型下(CC vs CT+TT)也发现与SLE有关(显性模型:OR=1.353,95%CI=1.174～1.561,P<0.001;隐性模型:OR=2.216,95%CI=1.695-2.898,P<0.001),但Meta分析发现中国人群-607位点A等位基因对SLE有保护效应(OR=0.606,95%CI=0.396～0.930,P<0.001)。结论欧裔人群中IL-18-1297和-607位点多态性可能与SLE易感性有关,中国人群的IL-18-607位点A等位基因对SLE可能有保护效应。     

类风湿关节炎药物治疗基因多态性研究进展

类风湿关节炎(RA)是一种系统性疾病,可致关节破坏和残疾.治疗以传统DMARDs和生物制剂为主.药物疗效与患者基因多态性密切相关.药物主要包括甲氨蝶呤、来氟米特、柳氮磺胺吡啶和生物制剂如TNF拮抗剂、妥珠单抗、力妥昔单抗等.RA患者遗传背景是影响药物疗效的重要因素,必然对个体化治疗产生深远影响,因而研究基因多态性与RA患者疗效反应的相关机制具有重要意义.     

云南人群中PTPN22和PADI4基因多态性与类风湿关节炎的关联研究

目的 探讨云南人群PTPN22和PADI4基因的7个SNP多态与类风湿关节炎易感性的相关性.方法 选取192例类风湿关节炎患者和288名正常人进行病例对照研究.分别用PCR-RFLP法检测PTPN22基因的rs33996649和1858位点、PADI4基因的rs11203366和rs874881位点,用焦磷酸测序法检测PADI4基因的rs1635579、rs2428736和rs2240340共7个SNP位点的基因型.结果 在7个SNP位点中,PADI4基因的rs2240340位点的等位基因频率和基因型频率在病例组和对照组间差异有统计学意义(P＜0.05).结论 在云南人群中PADI4基因的rs2240340多态性与类风湿关节炎的易感性存在相关性.     

IL-17和IL-35水平与甲状腺癌关系的Meta分析

目的 探讨白细胞介素(interleukin,IL)-17和IL-35水平与甲状腺癌的关系.方法 应用计算机检索PubMed、中国知网和万方数据库自200年1月至2016年12月关于IL-17和IL-35水平与甲状腺癌关系的临床对照试验.按纳入和排除标准选择文献,提取数据.采用Stata12.0软件对纳入文献进行Meta分析.结果 纳入文献5篇,样本量409例.与对照组比较甲状腺癌患者IL-17水平明显增加[WMD=6.31, 95%CI(5.89, 6.73)],而IL-35水平明显减低[WMD=-8.52, 95%CI(-9.40, -7.63)],其差异均具有统计学意义(P均<0.05).结论 现有证据表明IL-17和IL-35水平与甲状腺癌的关系密切,其可为甲状腺癌的诊断、治疗和预后提供依据.     

Interleukin-17A rs2275913, Interleukin-17F rs763780 and rs2397084 gene polymorphisms as possible risk factors in Juvenile lupus and lupus related nephritis

There are no reports about the association of interleukin (IL)-17A and IL-17F gene polymorphism and susceptibility to pediatric systemic lupus erythematosus (pSLE). Objective: To examine the possible role of IL-17A rs2275913, IL-17F rs763780 and rs2397084 polymorphisms as risk factors for pSLE in a cohort of Egyptian children and to investigate their association with the clinico-pathological features including lupus nephritis (LN). Methods: Typing of IL-17A and IL-17F polymorphisms was done using restriction fragment length polymorphism for 115 children with SLE and 259 age- and sex-matched healthy controls. Results: No significant differences were found between pSLE patients and healthy controls for the allele and genotype frequencies of IL-17A rs2275913, IL-17F rs763780 and rs2397084 (p?>?0.05). However, the combined genotype GGAGAA and the haplotype GGA had significant association with pSLE (p_c?=?0.042 and <0.001, respectively). The AA genotype of IL-17F rs763780 is more frequent in female patients (p?=?0.002) and the AA genotype of IL-17F rs2397084 is more associated with positivity of ds-DNA (p?=?0.007). No more associations were found for the demographic and clinical data of pSLE patients including risk of LN development, risk of non-remission, overall survival, activity and chronicity indices. Conclusion: The GGAGAA combined genotype and the GGA haplotype of IL-17A rs2275913, IL-17F rs763780 and rs2397084 can be considered risk factors for the development of SLE in Egyptian children. IL-17A rs2275913, IL-17F rs763780 and rs2397084 are not related to the LN development, SLE disease activity or overall survival.     

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4(+) T-helper 17 (Th(17)) cells, whereas IL-12 negates IL-17A production by promoting Th(1)-cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml(-1) vs 176.11 ± 277.32 pg ml(-1); P = 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.     

Association of two polymorphisms rs2910164 in miRNA-146a and rs3746444 in miRNA-499 with rheumatoid arthritis: A meta-analysis

Background

It has been reported that two single nucleotide polymorphisms (SNPs) rs2910164 in miRNA-146a and rs3746444 in miRNA-499 might be associated with the susceptibility to rheumatoid arthritis (RA). Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the two SNPs and RA risk.

Methodology/main results

A systematic search of studies on the association of two SNPs with susceptibility to RA was conducted in PubMed and Embase. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. A total of 6 case-control studies on rs2910164 and 3 studies on rs3746444 were included. Though no evidence of association was found between rs2910164 polymorphism and RA risk in all the genetic models, a trend of reduced risk could be drawn. (C versus G: OR = 0.93, 95% CI 0.82–1.05; GC versus GG: OR = 0.89, 95% CI 0.73–1.10; CC versus GG: OR = 0.84, 95% CI 0.64–1.10; GC/CC versus GG: OR = 0.89, 95% CI 0.73–1.08; CC versus GC/GG: OR = 0.94, 95% CI 0.77–1.14). A significant increased risk of RA was observed in the rs3746444 polymorphism in homozygote comparison, recessive comparison, and allele comparison, but there was insufficient data to fully confirm the association of RA and rs3746444 in miRNA-499.

Conclusions

MiRNA-146a rs2910164 polymorphism is not associated with RA risk, while miRNA-499 rs3746444 polymorphism is correlated with RA risk. However, the results of miRNA-499 rs3746444 should be interpreted with caution due to limited sample and heterogeneity. Large-scale and well-designed studies are needed to validate our findings.     

Association of IL-17A and IL-17F polymorphisms with gastric cancer risk in Asians: A meta-analysis

Increasing number of studies focused on the association of IL-17A rs2275913 and IL-17F rs763780 polymorphisms with gastric cancer (GC) risk. However, the results were inconsistent. To elucidate the exact association, we performed the present meta-analysis. Databases including PubMed, Web of knowledge and Chinese National Knowledge Infrastructure (CNKI) were systematically searched for potentially eligible literatures. Odds ratios (OR) and their 95% confidence interval (CI) were used to evaluate the strength of association. Eight studies for IL-17A rs2275913 (3345 cases and 4427 controls) and five studies for IL-17F rs763780 (1784 cases and 2592 controls) were finally included. The results indicated that individuals with AA genotype of IL-17A rs2275913 polymorphism were associated with increased GC risk compared with wild-type GG (OR = 1.61, 95% CI = 1.17–2.23, P = 0.004); A allele was significantly associated with increased GC risk compared with G allele (OR = 1.22, 95% CI = 1.06–1.41, P = 0.007). IL-17F rs763780 polymorphism was also significantly associated with increased GC risk (CC vs. CT: OR = 1.40, 95% CI = 1.04–1.88, P = 0.025; CT vs. TT: OR = 1.35, 95% CI = 1.16–1.58, P < 0.001; C allele vs. T allele: OR = 1.30, 95% CI = 1.15–1.47, P < 0.001). In summary, IL-17A rs2275913 A/G polymorphism and IL-17F rs763780 C/T polymorphism might be associated with increased GC risk in Asians. Further large-scale studies are still required to confirm the results of this meta-analysis.     

Association of PTPN22 rs2476601 and EGFR rs17337023 Gene polymorphisms and rheumatoid arthritis in Zahedan,Southeast Iran

In this study we aimed to evaluate the possible association of PTPN22 rs2476601 as well as epidermal growth factor receptor (EGFR) rs17337023 gene polymorphism and rheumatoid arthritis (RA) in a sample of Iranian population. This case‐control study was performed on 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood and PTPN22 rs2476601 and EGFR rs17337023 polymorphisms were determined using tetra amplification refractory mutation system–polymerase chain reaction (T‐ARMS‐PCR). The results showed that PTPN22 rs2476601 CT genotype as well as rs2476601 T allele was a risk factor for susceptibility to RA (OR=5.89 95%CI = 1.78–19.48, P = 0.004 and OR = 4.78, 95%CI = 1.59–14.35, P = 0.003, respectively). We also found that EGFR rs17337023 AT and rs17337023 TT genotypes were risk factor for susceptibility to RA (OR = 9.94 95%CI = 3.65–26.73, P < 0.001 and OR = 3.66, 95%CI = 1.46–9.15, P = 0.005, respectively). In addition the EGFR rs17337023 T allele was a risk for predisposition to RA (OR = 1.56, 95%CI=1.06‐2.30, P = 0.030). In conclusion, we found an association between PTPN22 rs2476601 and EGFR rs17337023 polymorphisms and the risk of RA in a sample of Iranian population.     

IL-6 promoter polymorphisms in rheumatoid arthritis

We investigated the possible association between the IL-6 promoter polymorphisms, at positions -622 and -174, and susceptiblity to, and/or outcome of, rheumatoid arthritis (RA). A total of 163 patients with RA and 157 healthy controls were genotyped for IL-6 using a PCR-RFLP method. The -622 and -174 alleles were in complete linkage disequilibrium. No difference was observed in the distribution of IL-6 promoter genotype or allele frequencies between RA patients and controls. However, a significant difference in the mean age at disease onset between IL-6 genotypes was observed. The present data appear to rule out an important role of IL-6 promoter polymorphisms in the susceptibility to RA. However, IL-6 genotypes may contribute to the pathogenesis of the disease by influencing the age at disease onset.     

核因子-κB受体激活因子配体基因多态性与类风湿关节炎易感性的研究

目的 研究中国汉族人群中核因子-κB受体激活因子配体(receptor activator of NF-κB ligand,RANKL) rs7984870基因多态性与类风湿关节炎(RA)发生危险因素关系.方法 采用以医院为基础的病例-对照研究,基质辅助激光解吸电离飞行时间质谱( matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,MALDI-TOF MS)技术分析214例RA患者和478例对照RANKLrs7984870 C＞G基因多态性,计算各种基因型的RA发生风险及其95%可信区间.结果 RANKL rs7984870 C＞G基因3种基因型CC、CG和GG在RA组和对照组的频率分别为27.3% (CC)、51.2% (CG)、21.5% (GG)和25.3% (CC)、49.1% (CG)、25.7% (GG),Logistic回归发现与携带RANKL rs7984870 CC基因型的个体相比较,携带RANKL rs7984870 GG等位基因型与RA的发病风险无明显相关(OR=0.78,95% CI=0.49 ～ 1.24).结论 RANKL rs7984870基因多态性可能不是RA发生的危险因素,需要进一步研究证实.     

Increased synovial expression of IL-27 by IL-17 in rheumatoid arthritis

Objectives and design

Interleukin (IL) 17 plays an important role in synovial inflammation and bone destruction in rheumatoid arthritis (RA), while IL-27 exerts a regulatory role in T cell-mediated immune responses. Our aim was to study the influence of IL-17 on IL-27 production in RA.

Materials and methods

Following injection of IL-17 in the knee joint of CIA mice, synovium was examined for IL-17 and IL-27 expression by western blot, real-time PCR, and immunohistochemistry. IL-17 and IL-27 levels were measured by ELISA in mouse bone marrow-derived dendritic cells (BM-DCs) and in synovial fluid (SF) macrophages from RA patients.

Results

IL-17 exacerbated disease progression in CIA mice. Histological analysis showed increased pannus formation associated with cartilage and bone erosion following injection with IL-17. The expression of IL-27 was increased in CIA mice. The expression of IL-17 and IL-27 was increased more in IL-17-injected CIA mice than in control mice. The majority of cells expressing IL-27 were co-localized with synovial macrophages. Increased expression of IL-27 by application of recombinant IL-17 was confirmed in CIA BM-DCs and in SF macrophages from RA patients.

Conclusion

IL-17 enhanced expression of IL-27 in synovial macrophages from RA patients and CIA mice, indicating an interaction between IL-17 and IL-27 as an autoregulatory mechanism.     

Association between polymorphisms in cytokine genes IL-17A and IL-17F and development of allergic rhinitis and comorbid asthma in Chinese subjects

Background

Th17 cell lineage, a distinct pro-inflammatory lineage characterized by preferential synthesis of cytokines IL-17A and IL-17F, is thought to play an important role in the pathogenesis of allergic rhinitis (AR).

Objectives

Our aim was to investigate whether polymorphisms in and around IL-17A and IL-17F genes are associated with AR and comorbid asthma.

Methods

A case-control comparison was performed in a cohort of 279 AR patients, 197 allergic rhinitis with asthma (AR-A) patients and 281 control Chinese subjects, to investigate associations between 19 tagging single-nucleotide polymorphisms (SNPs) in IL-17A and IL-17F gene regions and manifestation of AR or AR-A. Genotyping was performed using the Sequenom MassARRAY platform.

Results

SNP rs3819024 in IL-17A gene, intergenic SNPs rs1892280 and rs10807439 were specifically associated with AR protective or risk effects, while rs3819024 in IL-17A gene, intergenic SNP rs13192563 in IL-17F gene were associated with AR-A protective or risk effects. Haplotype analysis showed significant AR risk in haplotype AA (rs1892280G–rs13192563A) and AR protective effect in haplotype GT (rs7758579A–rs11966760T); the haplotype AT(rs7758579–rs11966760) were considered AR-A risk.

Conclusions

Our findings preliminarily indicate IL17A and IL17F SNPs, and some intergenic variants have the potential association with AR and comorbid asthma in Chinese population.