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。     

广东汉族类风湿关节炎某些易感基因研究

为了探讨类风湿关节炎（ＲＡ）的遗传易感基因，用多聚酶链反应－聚丙烯酰胺凝胶电泳（ＰＣＲ－ＰＡＧＥ）和银染色作ＨＬＡ－ＤＱＡ１基因分型，对１０６例健康人和５０例ＲＡ患者进行检测。结果显示：广东汉族共检出６种ＤＱＡ１等位基因，ＲＡ患者组ＤＱＡ１＊０１０１等位基因显著增高（ＲＲ＝２．３３４、Ｐ＜０．００５、ＥＦ＝０．１５４）；ＤＱＡ１＊０１０２明显减少（ＲＲ＝０．０６８、Ｐ＜０．０１、ＰＦ＝０．５７７）；对ＲＡ组中的３１例ＤＲ４阳性患者的ＤＱＡ１基因分析显示，ＤＲ４与ＤＱＡ１＊０３０１连锁的频率显著高于健康人组（Ｐ＜０．００５）。提示ＤＱＡ１＊０１０１对ＲＡ有易感作用，而ＤＱＡ１＊０１０２有遗传抵抗作用；ＤＱＡ１和ＤＲ４基因型检测可能为预测ＲＡ易感者和估计预后提供理论依据。     

应用CNV-Seq技术分析163例肠管回声增强胎儿的染色体拷贝数变异

目的评估低深度全基因组拷贝数变异测序技术(copy number variation sequencing, CNV-seq)在胎儿肠管回声增强(echogenic fetal bowel, EB)孤立型及合并其他超声软指标(合并型)中的诊断价值及遗传病因分析, 为临床遗传咨询提供指导。方法以2017年12月至2021年6月就诊于本中心共163例为研究对象。采集羊水(162例)或绒毛(1例)进行CNV-Seq检测, 结合生物信息学分析其致病性CNVs情况。结果 163例中共检出13例(8.0%)阳性, 包括9例(5.5%)非整倍体及4例(2.4%)CNVs。其中孤立型EB组和合并型EB组阳性率分别为1.7%(1/58)和11.4%(12/105), 经卡方检验, 两者存在显著差异(P<0.05)。两组中各发现一例Xp22.1重复, 为女性DMD携带者, 后健康出生。合并型EB组中发现9例非整倍体及2例致病性/疑似致病性CNVs, 均引产。结论合并型EB胎儿的非整倍体及致病性CNVs阳性率远高于孤立型EB, 且大部分终止妊娠。这提示在临床上相对于孤立型EB, 需要更加关注合并型EB...     

应用CNV-seq技术分析217例鼻骨发育不良胎儿的基因组拷贝数变异

目的评估低深度全基因组测序技术(copy number variations sequencing, CNV-seq)在鼻骨发育不良胎儿遗传学病因中的诊断价值。方法选择2017年12月至2020年12月本院发现的217例鼻骨发育不良胎儿为研究对象, 分为孤立型鼻骨发育不良组及合并其他异常组, 进行CNV-Seq检测, 并分析拷贝数变异(copy number variations, CNVs)的情况。结果在217例胎儿中共检出40例异常, 异常率为18.4%, 其中包括31例非整倍体(14.3%, 31/217)和9例CNVs(4.1%, 9/217)。孤立组共检出5例21三体(3.5%, 5/144)和2例临床意义未明CNVs(1.4%, 2/144)。合并组检出26例非整倍体(35.6%, 26/73), 包括19例21三体、6例18三体及1例13三体, 另发现5例致病性CNVs(6.8%, 5/73)以及2例临床意义未明CNVs(2.7%, 2/73)。经卡方检验, 两组差异具有统计学意义(P<0.01)。结论 CNV-Seq技术对于鼻骨发育不良的胎儿的染色体异常具有较高的...     

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。     

低深度拷贝数变异测序在孕早中期流产物检测中的临床价值

目的 通过对孕早中期流产物进行低深度全基因组拷贝数变异测序(CNV-seq),探讨该技术检测流产物染色体拷贝数变异的临床应用价值.方法 对2018年2月至2021年1月因胚胎停育或自然流产来我院行终止妊娠术取样的828例流产物进行低深度全基因组CNV-seq检测,STR进行母体污染鉴定.结果 828例流产物中,CNV-...     

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.     

全基因组测序用于肾脏异常胎儿的产前诊断CSCD

目的应用全基因组测序技术对4例肾脏异常胎儿进行遗传学检测,以寻找其可能的遗传学病因。方法对4例肾脏异常胎儿的孕妇抽取羊水及胎儿父母外周血进行DNA提取,行全基因组测序检测,根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)原则对数据进行判定,拷贝数变异结果与SNP-array结果进行比对,致病性点变异行Sanger测序验证。结果全基因组测序技术检测2例胎儿为拷贝数变异致病,分别为染色体17q12缺失1.45 Mb和1q21.1-21.2重复1.85 Mb;2例胎儿为基因变异致病,分别为PKHD1 c.8301del(p.Asn2768Thr fs*18)和c.4481del(p.Asn1494Thrfs*6)复合杂合变异和BBS12:c.1372dup(p.Thr458Asnfs*5)纯合变异。SNP-array和Sanger测序结果与全基因组测序数据一致。根据ACMG遗传变异分类标准与指南,PKHD1 c.8301del(p.Asn2768Thr fs*18)和c.4481del(p.Asn1494Thrfs*6)变异均为致病性变异(PVS1+PM2+PM3+PP4),BBS12:c.1372dup(p.Thr458Asnfs*5)变异判定为可能致病性变异(PVS1+PM2)。结论全基因组测序技术可以高效快速的为产前肾脏异常胎儿提供遗传学诊断,并为遗传咨询提供依据。     

类风湿关节炎的免疫治疗进展

近年来 ,类风湿关节炎 (RA)的免疫治疗取得了令人瞩目的进展。当前主要的免疫治疗包括 :针对炎症免疫介质 ,特别是细胞因子相关的治疗 ;针对细胞 ,尤其是T淋巴细胞的治疗 ;诱导抗原特异性耐受 ,如口服耐受 ;传统、免疫的联合疗法 ;其它治疗方法 ,如造血干细胞移植和基因治疗等。尽管RA免疫治疗还有待发展和完善 ,但是可以预言 ,免疫治疗将在RA治疗中揭开新的篇章     

The potential role of VPREB1 gene copy number variation in susceptibility to rheumatoid arthritis

Although the etiology of rheumatoid arthritis (RA) remains unknown, it has been widely suggested that RA has a genetic background. In humans, a copy number loss of 22q11.2, a region harboring the VPREB1 gene, has been suggested to be associated with several immunologic disorders, but there has been no study on the copy number variation (CNV) of the VPREB1 and its potential association with RA. Here, we explored the association between the RA and the CNV of the VPREB1 gene by performing genomic quantitative PCR and quantification of B cell subsets in RA patients and controls. The proportion of the individuals with <2 copies of the VPREB1 gene was significantly higher in the patient group than that in the controls (12.9% vs 0.9%, p < 0.0001), while that of the individuals with >2 copies was lower in the patient group than that in the controls (1.7% vs 18.9%, p < 0.0001). The odds ratio (OR) of the individuals with <2 copies was significantly higher compared with the odds ratio of those individuals with 2 copies (OR = 12.1, 95% confidence interval (CI) 2.8-51.6). Likewise, the OR of the individuals with >2 copies was significantly lower than the OR of those individuals with 2 copies (OR = 0.09, 95% CI 0.03-0.3). We also found that the proportion of CD21⁻CD23⁻ B cells was significantly higher in the RA patients compared with that of the controls (11.9% vs 5.7%, p = 0.002), but the proportion of CD21⁺CD23⁺ cells was significantly lower in the RA patients (26.2% in RA vs 34.9% in the controls, p = 0.005). To the best of our knowledge, this is the first evidence showing the association between a low copy number of the VPREB1 gene and RA, and this may help understanding the pathogenesis of RA and other autoimmune disorders.     

Muscle changes in rheumatoid arthritis

Summary Muscle changes were studied in biopsy material obtained from 100 patients suffering from classical rheumatoid arthritis. The abnormalities consisted of denervation atrophy of type II muscle fibres, degenerative changes in the sarcoplasm including presence of nemaline rods, and changes within the interstitium: namely perivascular nodular myositis, lymphocytic accumulations, different stages of vasculitis and abnormalities within the intramuscular nerves and muscle spindles. The muscles examined were always severely affected. It is considered that the simultaneous presence of these abnormalities is suggestive of rheumatoid arthritis. The importance of histochemical studies is emphasized. The literature concerning muscle changes in rheumatoid arthritis is reviewed.Temporary Research Fellow the Rotterdam Centre for Rheumatic Disease     

Comprehensive review of genetic association studies and meta-analysis on miRNA polymorphisms and rheumatoid arthritis and systemic lupus erythematosus susceptibility

BackgroundMicroRNAs (miRNAs), small RNA molecules, play a role in the development and differentiation of immune cells in both innate and adaptive immune responses. Our study was aimed to investigate the association between three miRNA polymorphism and rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) by using meta-analysis approach.MethodsA PubMed database search was conducted during August 2013 to identify case–control studies of miRNAs and RA or SLE risk. Two authors independently extracted information on the study design, the characteristics of the study participants, exposure and outcome assessments. The fix-effects and random-effects models were used for the risk estimates by Stata 11.0 software.ResultsOur meta-analysis of six case–control studies involving a total of 998 RA cases and 1493 controls identified no significant association between mir-146a rs2910164 and RA, with an overall OR of 0.843 (95% CI = 0.642–1.105; CC vs. GG). No association was observed in three studies with a total of 1532 cases and 2168 controls between miR-146a rs2910164 and SLE risk (OR = 0.911, 95% CI = 0.710–1.171; CC vs. GG). Three studies with a total of 529 cases and 595 controls evaluated the mir-499 rs3746444 polymorphism and its association with RA. There was a decreased overall risk of RA under the allelic and genotypic models [OR = 0.616, 95% CI = 0.384–0.981, (T vs. C allele) and OR = 0.386, 95% CI = 0.226–0.659, (TT vs. CC)]. Two studies with 4826 cases and 4181 controls evaluated miR-146a rs57095329 and its association with SLE. There was a significant association between miR-146a rs57095329 and SLE (OR = 1.263, 95% CI = 1.136–1.405, G vs. A allele).ConclusionsThe present meta-analysis suggests important roles for the mir-499 rs3746444 polymorphism in RA, especially in the Caucasian population and for miR-146a rs57095329 polymorphism in SLE. Further studies with large sample size are needed to confirm these associations.     

滑膜成纤维细胞在类风湿性关节炎发病中的作用

类风湿性关节炎是复杂的多系统疾病,近年来,越来越多的证据表明,滑膜成纤维细胞在类风湿性关节炎中过度增殖,介导炎症反应,造成关节结构破坏。滑膜成纤维细胞在类风湿性关节炎发病过程中具有重要的作用。     

抗类风湿性关节炎54 kD和36 kD自身抗体在类风湿性关节炎诊断中的意义

目的：研究类风湿性关节炎（ＲＡ）中抗类风湿性关节炎５４ｋＤ和３６ｋＤ自身抗体（抗ＲＡ５４和抗ＲＡ３６）的情况。方法：应用免疫印迹技术（ＩＢＴ）,在过筛和检测盐水可提取核抗原（ＥＮＡ）的自身抗体谱过程中,发现不仅可检测到抗ＲＡ５４,还可检测到抗ＲＡ３６自身抗体,并对１６９例各种不同风湿性疾病患者测定ＥＮＡ。结果：抗ＲＡ５４和抗ＲＡ３６自身抗体均仅见于类风湿性关节炎（ＲＡ）组（ｎ＝８０）,阳性率分别为１５．００％和６．２５％。结论：抗ＲＡ５４和抗ＲＡ３６对ＲＡ的诊断有高度特异性,Ｐ＜０．００５和Ｐ＜０．０１。     

Cytology of pleural effusions in rheumatoid arthritis

Rheumatoid pleural effusions are relatively uncommon. The cytologic examination of such effusions can be diagnostic of the underlying disease; this is of great clinical significance when the rheumatoid condition has not been diagnosed prior to the pleural involvement. The diagnostic cytologic abnormalities include large elongated and multinucleated giant cells and macrophages in a background of granular and necrotic debris. The cytologic characteristics parallel the histologic features of pleural rheumatoid nodules.     

白细胞介素-37在类风湿性关节炎患者血清表达水平的研究

目的 通过检测类风湿性关节炎(RA)患者血清中细胞因子白细胞介素(IL)-37、肿瘤坏死因子-α(TNF-α)、IL-18、炎性指标红细胞沉降率以及C-反应蛋白(C-reactionprotein,CRP)水平,观察RA患者临床数据包括压痛关节数,肿胀关节数以及DAS28评分等,探讨RA患者血清IL-37水平升高的意义以其在RA发病机制中可能的作用.方法 80例RA患者、80例健康对照患者,通过酶联免疫吸附试验(ELISA)法检测其血清中细胞因子水平.结果 RA患者血清中IL-37[(40.33±11.25)pg/mL]、TNF-α[(110.41 ±35.37) pg/mL]、IL-18[(121.73±29.22) pg/mL]水平以及红细胞沉降率(ESR)[(42.31±15.02) mm./h]、CRP[(38.31±17.22) mg/L]水平明显高于对照组IL-37[(18.21±5.72) pg/mL]、TNF-α[(30.19±6.82) pg/mL]、IL-18[(55.47±7.29) pg/mL]水平,组间差异有统计学意义(P＜0.05).IL-37的表达与TNF-α、IL-18水平呈正相关(相关系数r=0.981,P=0.001).结论 IL-37在RA患者体内高表达并与其它几种炎性因子的表达具有相关性,IL-37可能作为炎性抑制因子参与了RA的发生、发展.     

CD28 and PTPN22 are associated with susceptibility to rheumatoid arthritis in Egyptians

ObjectiveLimited data are available on the genetics of rheumatoid arthritis (RA) in Egyptians. Therefore, we investigated whether the confirmed genetic risk factors for RA in Europeans and/or Asians contribute to RA susceptibility in Egyptians.Subjects and methodsA set of seven single-nucleotide polymorphisms (SNPs) in the vicinity of CD28, TNFAIP3, PTPN22, PADI4 and HLA-DRA were tested in a large multi-centric RA cohort in Egypt, consisting of 394 cases and 398 matched controls. Patients were stratified based on the positivity of either anti-citrullinated protein antibodies (ACPAs) or rheumatoid factor (RF).ResultsSignificant association was evident for three SNPs in this cohort: the CD28 (rs1980422) variant showed a strong association in the whole cohort (P = 0.000119) and in seropositive subsets of the disease (P_ACPA+ = 0.004; P_RF+ = 0.0005). Upon stratification, the PTPN22 (rs2476601) and TNFAIP3(rs5029939) variants showed association only with ACPA positive (P_ACPA+ = 0.00573) and negative (P_ACPA− = 0.00999) phenotypes, respectively.ConclusionOur results suggest that CD28(rs1980422) and PTPN22(rs2476601) contribute to RA-susceptibility in Egyptians. Failure to replicate the association of PADI4(rs2240340)/(PADI4_94) in Egyptian RA patients provides further support for the notion that genetic architecture of RA is different in multiple populations of European, Asian, African, and Middle Eastern ancestries. Further investigation using large-scale studies is thus needed to maximize the power of genetic association.     

Association between KIR gene polymorphisms and rheumatoid arthritis susceptibility: A meta-analysis

ObjectivesThe results of studies on association between KIR (killer cell immunoglobulin-like receptors) polymorphisms and susceptibility to RA (rheumatoid arthritis) are inconsistent. To comprehensively evaluate the effect of KIR polymorphisms on the risk of RA, a meta-analysis was carried out.MethodsThe Web of Science, PubMed, the Chinese Biomedical Database (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to select studies on the association between KIR polymorphisms and RA. The odds ratio (OR) with 95% confidence interval (95%CI) was obtained.ResultsNine qualified case–control studies were included in this meta-analysis. The results showed there were two positive associations of 2DL1, 2DS1 (OR_2DL1 = 2.20, 95%CI = 1.20–4.01, P_raw = 0.01, P_FDR = 0.03; OR_2DS1 = 1.84, 95%CI = 1.19–2.85, P_raw = 0.006, P_FDR = 0.018) and one negative association of 2DL3 (OR_2DL3 = 0.42, 95%CI = 0.22–0.79, P_raw = 0.006, P_FDR = 0.018) with susceptibility to RA in East Asians, but not in Caucasians.ConclusionThe current meta-analysis provides evidence that 2DL3 might be a potential protective factor and 2DL1, 2DS1 might be risk factors for RA in East Asians but not in Caucasians.     

Macrophage activation syndrome in a child with systemic juvenile rheumatoid arthritis

Macrophage activation syndrome (MAS) is a rare and potentially fatal complication of rheumatic disorders in children. We describe a 13-month-old boy in whom MAS developed as a complication of systemic juvenile rheumatoid arthritis (S-JRA). He suffered from fever and generalized rash followed by multiple joints swelling for four months before admission. Physical examination revealed cervical lymphadenopathy and hepatosplenomegaly. Laboratory findings were: abnormal liver enzymes, increased triglyceride and ferritin levels, coagulopathies resembling disseminated intravascular coagulation, anemia and thrombocytopenia. Hyperplasia of hemophagocytic macrophages was remarkable in his bone marrow. Methylprednisolone and cyclosporin therapy resulted in clinical and laboratory improvements. This is the third case of MAS associated with S-JRA in Koreans, and the first one, in which hemophagocytic macrophages were proven in bone marrow.