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Abstract：
Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2⁻3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2⁻2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.
摘要：
我们的目的是分析（i）类风湿关节炎（RA）患者JUN和FOS核心启动子中单核苷酸多态性（SNP）的存在，膝骨关节炎（OA），和正常对照（NC）；（ii）它们对JUN/FOS转录水平的功能影响；（iii）它们与RA或膝OA的发生的关联。使用非同位素RNA酶切割测定(NIRCA)在初始筛选群体中鉴定JUN和FOS启动子SNP;使用报告基因测定分析它们的功能影响。在RA中进行基因分型(n=298)，膝OA（n=277），和NC(n=484)样品。对于复制，在芬兰队列中验证了显著关联(OA:n=72,NC:n=548).最初，在JUN启动子中检测到两个SNP，在FOS启动子中检测到另外两个SNP处于完全连锁不平衡（LD）。JUN启动子SNPrs4647009引起报告基因表达的显著下调，而报告基因表达在FOS启动子SNP存在下显著上调。FOS启动子SNP的纯合基因型与膝关节OA的易感性相关(比值比(OR)2.12,95%置信区间(CI)1.2-3.7,p=0.0086)。这种关联在芬兰健康2000年研究队列中成功复制（等位基因OR1.72，95％CI1.2-2.5，p=0.006）。FOS启动子变体可以代表膝关节OA的相关易感性标记。
