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。     

Association Study of Matrix Metalloproteinases Gene Polymorphisms with Susceptibility to Rheumatoid Arthritis: A Meta-Analysis

Objective: Association of matrix metalloproteinases (MMPs) gene polymorphisms with rheumatoid arthritis is controversial. We conduct a meta-analysis to clarify this dispute.

Methods: We systematically searched the electronic PUBMED, EMBASE and CNKI databases for research articles about MMPs (MMP-1, MMP-2, MMP-3, MMP-9) gene polymorphisms and rheumatoid arthritis (RA) up to January 2015. According to the heterogeneity, fixed-effects or random-effects models were used to calculate crude odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: A total of 11 articles involving 2143 cases and 2049 controls were included in this meta-analysis. Overall, no significant associations were observed between MMP-1-1607 1G/2G polymorphism and RA. Stratification by ethnicity, no significant associations were observed in Caucasian populations. Similarly, no significant associations were observed between MMP-3-1171 5A/6A, MMP-9-1562 C/T polymorphisms and RA in overall and Caucasian populations, respectively. However, a weak association was found between MMP-2-1306 C/T polymorphism and RA (C vs. T, OR?=?0.813, 95%CI?=?0.694–0.953, p?=?0.010) in overall populations.

Conclusions: The present meta-analysis suggests that MMP-1-1607 1G/2G, MMP-3-1171 5A/6A, MMP-9-1562 C/T polymorphisms are not associated with the susceptibility of RA, but MMP-2 -1306 C/T is weakly associated with susceptibility to RA. Further studies with more sample size are needed for definitive conclusions.     

MTHFR基因多态性与银屑病的遗传易感性

【摘要】　目的　探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因单核苷酸多态与中国北方地区银屑病的关系。方法　针对123例寻常型银屑病患者和129名正常对照个体,分别用PCR-RFLP和AS-PCR的方法,分析C677T、G1793A和A1298C 3个多态位点基因型,并进行统计分析。 结果 在病例组中,MTHFR 677 C、T等位基因频率分别为45.13%、54.87%,1298A、C等位基因频率为88.37%、11.63%,1793G、A等位基因频率为95.12%、4.88%。在正常对照组中,677 C、T等位基因频率分别为44.96%、54.87%,1298A、C等位基因频率为86.44%、13.56%,1793G、A等位基因频率为96.12%、3.88%。经统计学分析,MTHFR C677T 、A1298C、G1793A 各多态位点基因型、等位基因频率在病例组和对照组中的分布差异无显著性意义,C677T与A1298C基因型联合分析也未发现有统计学意义。结论 MTHFR基因的3个多态位点（C677T、A1298C、G1793A）与寻常型银屑病无明显的相关关系,可能与寻常型银屑病的易感性无关。     

补体系统基因单核苷酸多态性及其与疾病的关系

天然免疫系统在病原微生物入侵的初始阶段发挥着重要的防御作用,其中补体系统可快速识别、杀伤和清除病原微生物,对疾病的发生、发展和转归起着重要的作用.文章综述了补体系统各成份单核苷酸多态性与疾病的关联研究进展,在DNA水平上揭示了补体系统遗传多态性对疾病发生、发展和转归的影响,对疾病的预防和个体化治疗具有重要的意义.     

BARD1单核苷酸多态性与汉族儿童神经母细胞瘤相关性的研究

目的 探讨BARD1单核苷酸多态性与汉族儿童神经母细胞瘤的相关性.方法 采用病例对照研究,收集242例汉族神经母细胞瘤患儿及301例汉族健康儿童的外周血,通过PCR方法扩增目的DNA,应用Sequenom massarray对所扩增的DNA进行基因分型.以x2检验及logistics分析比较不同组基因型与神经母细胞瘤的关系.结果 BARD1的21个标签SNPs位点均符合Hardy-Weinberg平衡,BARD1的21个SNPs等位基因频率在患者组与对照组之间差异均无统计学意义(P＞0.05).结论 未发现BARD1单核苷酸多态性与汉族儿童神经母细胞瘤有相关性.     

Ficolin Gene Polymorphisms in Systemic Lupus Erythematosus and Rheumatoid Arthritis

Systemic lupus erythemathosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases characterized by an immune balance breakdown and by chronic inflammation. Several findings link SLE and RA development with the complement system and ficolin components have emerged as candidates for disease development. Since genetic association studies with ficolin genes in SLE and RA have not yet been conducted in a Brazilian population, the aim of this study was to determine whether polymorphisms of ficolin‐1(FCN1) and ficolin‐2 (FCN2) genes are associated with SLE and RA susceptibility as well as disease manifestation. Two SNPs within FCN1 (rs2989727 and 1071583) and three in FCN2 (rs17514136, rs3124954, and rs7851696) were studied in 208 SLE and184 RA patients as well as 264 healthy individuals in a Southeast Brazilian population. For SLE patients, the FCN2 rs17514136 SNP was associated with a more severe disease (SLICC) (p = 0.0067). Furthermore, an association between the occurrence of nephritis and the T/T genotype for FCN2 rs3124954 SNP (p = 0.047, OR = 3.17, 95%CI = 1.34–7.5) was observed. No association was observed between the studied polymorphisms and RA development. Thus, our data support involvement of the FCN2 gene in the SLE phenotype.     

Association of AIRE Polymorphisms with Genetic Susceptibility to Rheumatoid Arthritis in a Chinese Population

Recently, genetic polymorphisms within the autoimmune regulator (AIRE) have been implicated in the genetic susceptibility to rheumatoid arthritis (RA) in Japanese and Spanish. The aim of this case–control study involving 232 patients with RA and 313 ethnically matched control subjects was to investigate the association of AIRE rs2075876 and rs760426 polymorphisms with genetic predisposition to RA in a Chinese population. The genotypes of AIRE rs2075876 and rs760426 polymorphisms were determined by SNaPshot assay. A significant difference in the allele frequency of AIRE rs2075876 polymorphism between cases and controls was detected (A versus G, OR 1.33, 95 %CI 1.04–1.69, P?=?0.02, P corrected (Bonferroni correction) Pc?=?0.04). Significant evidence was found for the association between the minor allele A of AIRE rs2075876 polymorphism and the risk of RA under the recessive model (AA versus AG?+?GG, P?=?7.15?×?10^?3, Pc?=?1.43?×?10^?2). The frequency of the minor allele G of AIRE rs760426 polymorphism was higher in patients compared with controls (47.8 % versus 42.1 %), and this deviation showed a trend towards significant level (P?=?0.06, Pc?=?0.12). The association between the minor allele G of AIRE rs760426 polymorphism with RA risk under the dominant model and the recessive model revealed that significant evidence was detected under the recessive model (GG versus GA?+?AA, P?=?0.02, Pc?=?0.04). Our results indicated that AIRE rs2075876 and rs760426 polymorphisms were involved in the genetic background of RA in the Chinese population.     

Association of Single Nucleotide Polymorphisms in the MD-2 Gene Promoter Region With Der p 2 Allergy

Purpose

Sensitization to house dust mite (Dermatophagoides pteronyssinus) is a considerable risk factor for the progression of allergic disease. The group 2 allergen from Dermatophagoides pteronyssinus, Der p 2, is considered a major one in patients with specific immunoglobulin E (IgE) to Der p 2. Der p 2 has structural homology with myeloid differentiation 2 (MD-2), which is involved in the lipopolysaccharide-binding component of the Toll-like receptor 4 signaling pathway and the development of inflammation. The aim of this study was to examine the genetic association of single nucleotide polymorphisms (SNPs) in the promoter region of MD-2 with Der p 2-sensitive allergy.

Methods

We investigated associations between cohort''s characteristics, including 280 allergic and 80 healthy subjects by examining total IgE, eosinophils, D. pteronyssinus-specific IgE, Der p 2-specific IgE, the number of IgE-producing B cells induced by Der p 2, and the odds ratio of allergic symptoms.

Results

Based on the 1,000 genome project data, the minor allele frequencies of the rs1809441 and rs1809442 are 0.467 and 0.474, respectively. However, the correlation of linkage disequilibrium (LD) between these 2 SNPs is D''=1, the genotype frequencies of the 2 MD-2 (LY96) SNPs (rs1809441 and rs1809442) that are located nearby were significantly different between allergic and health subjects: the TT genotype of rs1809441 and the GG genotype of rs1809442 were more frequent in allergic subjects than in healthy subjects (16.1% vs 2.5% in both genotypes). The allergic patients with these genotypes exhibited significantly higher levels of D. pteronyssinus-specific IgE and Der p 2-specific Ig E, and a larger number of Der p 2-activated B cells. In addition, these 2 SNPs in the MD-2 promoter region were significantly associated with the prevalence of nasal, skin, and asthmatic allergic symptoms.

Conclusions

Our results indicated that 2 SNPs in the MD-2 promoter region were significantly associated with Der p 2-specific Ig E, and thereby suggest that these SNPs may play a major role in susceptibility to Der p 2-triggered immune responses in a Taiwanese population.     

Polymorphisms in the CTLA-4 Gene and Rheumatoid Arthritis Susceptibility: A Meta-analysis

Introduction

The +49A/G polymorphism and CT60 polymorphism in the CTLA-4 gene have been extensively examined for the association with rheumatoid arthritis (RA); however, results of different studies have been inconclusive. The aim of this study is to comprehensively evaluate the genetic risks of +49A/G and CT60 polymorphisms in the CTLA-4 gene for RA.

Methods

A meta-analysis was carried out to analyze the association of +49A/G and CT60 polymorphisms with RA risk.

Results

A total of 30 case?Ccontrol studies in 20 articles were included in this meta-analysis. The results indicated that the variant G allele carriers (GG + GA) of +49A/G polymorphism had an 18% increased risk of RA when compared with the homozygote AA (odds ratio (OR)?=?1.18, 95% confidence interval (CI): 1.04?C1.34 for GG + AG vs. AA). In addition, the variant CT60 A allele carriers of CT60 polymorphism had a 14% decreased risk of RA when compared with the homozygote GG (OR?=?0.86, 95%CI?=?0.78?C0.95 for AA + AG vs. GG). In the subgroup analysis by ethnicity, significant elevated RA risks were associated with +49G allele carriers in Asians, but not in Europeans. However, for CT60 polymorphism, significant decreased RA risks were associated with CT60 A allele carriers in Europeans, but not in Asians.

Conclusions

This meta-analysis suggested that the +49A/G and CT60 polymorphisms in the CTLA-4 gene may be risk factors for RA.     

类风湿性关节炎患者Eotaxin-3 +2497基因多态性研究

目的:研究类风湿性关节炎(RA)患者Eotaxin-3 +2497T/G单核苷酸多态性(SNP)。方法:用聚合酶链反应方法对目的基因进行扩增,用单链构象多态性方法进行SNP分析,最后用测序及四引物聚合酶链反应方法对结果进行验证。结果:RA组与对照组Eotaxin-3 +2497位存在TT和TG两种基因型,且基因型分布符合Hardy-Weinberg平衡定律;RA组与对照组Eotaxin-3 +2497位基因型频率及等位基因频率间差异有显著性意义(P<0.05)。结论:RA患者Eotaxin-3 +2497位G等位基因频率明显高于对照组。     

High-Throughput Genotyping with Single Nucleotide Polymorphisms

To make large-scale association studies a reality, automated high-throughput methods for genotyping with single-nucleotide polymorphisms (SNPs) are needed. We describe PCR conditions that permit the use of the TaqMan or 5' nuclease allelic discrimination assay for typing large numbers of individuals with any SNP and computational methods that allow genotypes to be assigned automatically. To demonstrate the utility of these methods, we typed >1600 individuals for a G-to-T transversion that results in a glutamate-to-aspartate substitution at position 298 in the endothelial nitric oxide synthase gene, and a G/C polymorphism (newly identified in our laboratory) in intron 8 of the 11-beta hydroxylase gene. The genotyping method is accurate-we estimate an error rate of fewer than 1 in 2000 genotypes, rapid-with five 96-well PCR machines, one fluorescent reader, and no automated pipetting, over one thousand genotypes can be generated by one person in one day, and flexible-a new SNP can be tested for association in less than one week. Indeed, large-scale genotyping has been accomplished for 23 other SNPs in 13 different genes using this method. In addition, we identified three "pseudo-SNPs" (WIAF1161, WIAF2566, and WIAF335) that are probably a result of duplication.     

单核苷酸多态性检测技术进展与全基因组关联研究

单核苷酸多态性(Single nucleotide polymorphism,SNP)是第三代遗传标记,在基因定位、遗传疾病等研究中发挥着重要作用.随着SNP检测技术的发展,在大规模人群中研究全基因组的变异位点与复杂疾病的关系已经成为可能.文章系统地介绍了全基因组关联研究(whole genome association,GWA)中所采用的几种高通量的SNP检测技术、原理、基因芯片及其商品信息,并对SNP技术在GWA研究中亟待解决的问题进行了阐述.     

RANTES Gene Polymorphisms Are Not Associated with Rheumatoid Arthritis and Atopic Dermatitis: A Meta-Analysis

Background: A few recent studies have suggested that regulated on activation, normal T cell expressed and secreted (RANTES) polymorphisms (-403 G/A, -28C/G) are associated with rheumatoid arthritis (RA) and atopic dermatitis (AD). However, there still existed studies that did not confirm this correlation. Objective: The objective of this study was to evaluate the relationships of RANTES and RA and AD using a meta-analysis. Methods: Pubmed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers, and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Results: Eight studies were enrolled, including a total of 548 RA cases and 493 controls of -403G/A, 305 RA cases and 303 controls of -28C/G, and 705 AD cases and 578 controls of -403G/A in this meta-analysis. In RA, the overall OR and 95% CI of -403A were 1.41, 1.10–1.82 (p = 0.391) and 2.18, 1.30–3.66 (p = 0.335) in dominant and recessive models, respectively. The overall OR and 95% CI of -28G in RA were 1.35, 0.91–2.01 (p = 0.707) and 3.32, 1.29–8.52 (p = 0.559) in dominant and recessive models, respectively. Moreover, the overall OR and 95% CI of -403A in AD were 1.38, 1.08–1.76 (p = 0.421) and 1.06 and 0.65–1.72 (p = 0.361) in dominant and recessive models, respectively. Conclusions: This meta-analysis showed that RANTES -403G/A and -28C/G were not associated with RA and AD.     

HLA Polymorphisms and T Cells in Rheumatoid Arthritis

A dense infiltrate of activated T cells, macrophages, and B cells in the synovial membrane is the cardinal pathological feature of rheumatoid arthritis (RA). Frequently, tissue infiltrating cells acquire a morphological organization reminiscent of secondary lymphoid tissue. The composition of the inflammatory lesions, the production of autoantibodies, and the association of disease risk with genes related to the HLA-D region have all been cited as evidence for a critical role of T cells in disease pathogenesis. Investigations on the precise role of HLA genes in RA have confirmed the importance of this genetic risk factor and have identified a consensus sequence within the HLA-DRB1 genes. The observation that HLA polymorphisms are mostly associated with disease progression and severity and that a gene dose effect for HLA-DR genes is operational has challenged the simple model that HLA molecules select and present an arthritogenic antigen. Studies analyzing the repertoire of tissue infiltrating T cells have not been able to identify a dominant and common disease relevant T cell. The infiltrate is diverse in terms of T cell receptor gene usage but consistently includes clonally expanded populations. Recent evidence indicates that RA patients carry expanded CD4 clonotypes which are characterized by deficient CD28 expression and autoreactivity. These autoreactive CD4 T cells are not restricted to the joint, raising the possibility that rheumatoid synovitis is a manifestation of a systemic autoimmune disease. Support for this model has come from studies in T cell receptor (TCR) transgenic animals which develop inflammation of the synovial membrane stimulated by a T cell response to ubiquitously expressed self-MHC molecules. Antigens driving the chroaic persistent immune response in RA may not be restricted to the joint but rather may be widely distributed, providing an explanation for the difficulties in identifying arthritogenic antigens directly or indirectly through the selection of joint infiltrating T cells.     

Evidence for Non-additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

We analyzed 13 single nucleotide polymorphisms (SNPs) within the apolipoprotein E (APOE) gene, to identify pairs of SNPs that interact in a non‐additive manner to influence genotypic mean levels of the ApoE protein in blood. An overparameterized general linear model of two‐SNP genotype means was applied to data from 456 female and 398 male unrelated European Americans from Rochester, MN, USA. We found statistically significant evidence for non‐additivity between SNPs within the male sample, but not within the female sample. We observed nine pairs of SNPs with evidence of non‐additivity at the α= 0.05 level of statistical significance within the male sample, when approximately three were expected by chance. Five of the nine pairs involved three SNPs (560, 624 and 1163) that did not have a statistically significant influence when considered separately in a single‐site analysis. Three of the nine pairs involving four SNPs (832, 1998, 3937 and 4951) showed significant evidence for non‐additivity in at least one of two other male samples from Jackson, MS, USA and North Karelia, Finland. Although all four of these SNPs had a statistically significant influence in Rochester when considered separately, only SNP 3937 gave a significant result in the other male samples. The four SNPs are located in the promoter, intronic and exonic regions, and 3' to the polyadenylation signal in the APOE gene. Our study suggests that analyses that only consider SNPs located in exons and ignore contexts such as those indexed by gender and population, and disregard non‐additivity of SNP effects, may inappropriately model the contribution of a gene to the genetic architecture of a trait that has a complex multifactorial etiology.     

HLA-B27 in Rheumatoid Arthritis and Amyloidosis

To study the role of genetically determined immune responsiveness in the pathogenesis of systemic amyloidosis complicating rheumatoid arthritis the HLA antigens were identified in 26 patients with rheumatoid arthritis complicated by secondary amyloidosis, in 44 patients with rheumatoid arthritis, and in 11 patients with secondary amyloidosis of non-rheumatoid origin. Subjects with ankylosing spondylitis, sacroiliitis without peripheral polyarthritis, Reiter's disease, reactive arthritis, erosive osteoarthritis, psoriatic arthropathy, systemic lupus erythematosus or arthritis associated with a gastrointestinal involvement were excluded from the study. Patients with amyloidosis secondary to rheumatoid arthritis had a high frequency of the HLA specificity B27 and of the haplotype likely to bear A2, B27. The association with B27 was closest in the group of male patients with amyloidosis whose rheumatoid arthritis had begun at an early age and who lacked demonstrable rheumatoid factor in serum. These patients may represent a genetically determined subentity of rheumatoid arthritis.     

2型糖尿病患者肝脂肪酶基因标签单核苷酸多态性与血脂水平分析

观察汉族人群肝脂肪酶(HL)基因2个标签单核苷酸多态性(SNP)与2型糖尿病(T2DM)及血脂代谢的相关性.应用荧光标记单碱基延伸分型技术及寡核苷酸微阵列芯片杂交技术检测HL基因rs 12462668和rs10426971多态性.用全自动生化分析仪检测CHO、TG、HDL-C、LDL-C、载脂蛋白Al( ApoAl)及...     

Association between IL‐17F Gene Polymorphisms and Susceptibility to and Severity of Rheumatoid Arthritis (RA)

Interleukin‐17F (IL‐17F) is a novel proinflammatory cytokine. IL‐17F gene is an excellent candidate for chronic inflammatory disease. We investigated the association between rheumatoid arthritis (RA) and His161Arg (7488A/G; rs763780) and Glu126Gly (7383A/G; rs2397084) polymorphism of IL‐17F gene. The gene polymorphisms in 220 Polish patients with RA and 106 healthy subjects were amplified by polymerase chain reaction with restriction endonuclease mapping. Overall, the polymorphisms of the IL‐17F gene were not correlated with susceptibility to RA in Polish population. However, the IL‐17F His161Arg variant was associated with parameters of disease activity, such as number of tender joints, HAQ score or DAS‐28‐CRP. Moreover, our findings have shown that Glu126Gly IL‐17F gene polymorphism may be correlated with longer disease duration in patients with RA. Our results for the first time showed the relationship between IL‐17F gene polymorphisms and severity of RA.     

Gene Therapy for Rheumatoid Arthritis

Rheumatoid arthritis (RA) was one of the earliest targets for gene therapy. Since the first clinical trial involving gene therapy in RA was initiated in 1996, eight clinical trials have been conducted assessing gene therapy in RA. Gene therapy has benefited from advances in biologics in terms of the increasing choice of novel, efficient targets to treat RA and also from the optimization of the delivery systems. Several strategies are possible; one of particular interest is local gene therapy directed to rheumatic joints, which avoids systemic vector diffusion. In this review, we discuss (i) gene therapeutic approaches that have been attempted for patients with RA, and (ii) novel strategies that are in development for delivery into patients. We analyze the advantages and disadvantages of the various approaches and how best to optimize them with regard to choosing the most promising vectors and strategies to allow for efficient, long-term, safe delivery of gene therapy in RA.