Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Almokhayam Aldaem Street, 6th Province, Nasr City, Cairo, 13465, Egypt.
Rheumatology, Rehabilitation and Physical Medicine Department, Faculty of Medicine (Boys), Al-Azhar University, Cairo, Egypt.
Clin Rheumatol. 2021 Jul;40(7):2927-2937. doi: 10.1007/s10067-021-05584-z. Epub 2021 Jan 18.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder, which can cause progressive and functional disability. Previous data suggests that some inflammatory cytokines are dysregulated in patients with RA. Polymorphisms in the NFKB1 gene were studied in different populations with RA. Specific studies showed that the NFKB1 promoter -94ins/delATTG (rs28362491) polymorphism appears to be correlated with alterations in the IL-6 expression and may lead to disease development. We aimed to evaluate the association between the NFKB1 -94ins/delATTG polymorphism and biochemical, and clinical markers for severity of RA in Egyptian patients.
Study subjects included 196 RA patients from the Egyptian population. NFKB1 -94ins/delATTG polymorphism was genotyped by real-time PCR using the TaqMan assay. Concentrations of plasma IL-6 were assessed using the ELISA method.
The frequencies of (del/del + ins/del) genotype in cases with erosive arthritis were significantly increased as compared to cases with non-erosive arthritis (63.0% vs. 47.7%, OR = 1.86, 95% CI: 1.05-3.30, p: 0.043). Carriers of del allele had high activity and severity markers compared with those of ins/ins genotype. The del allele was significantly associated with higher IL-6 levels in a dose-dependent manner. Plasma levels of IL-6 were significantly higher in the del/del (41.4 ± 16.2 pg/ml) and ins/del (19.1 ± 12.4 pg/ml) genotype when compared with the ins/ins genotype (11.4 ± 4.21 pg/ml). In a multivariate analysis of variance, including confounding factors associated with higher IL-6 levels (RF, disease duration, and DAS28), the NFKB1 -94ins/delATTG polymorphism retained its role. Logistic regression analyses revealed that high IL-6 plasma levels independently associated with an increased risk of presenting erosive RA, while -94ins/delATTG polymorphism has no direct association with the progression of erosive arthritis.
Our data indicate that the NFKB1 -94ins/delATTG polymorphism contributes to the severity and progression of RA through IL-6 levels modulation in Egyptian patients. Key Points • Carriers of del allele had high activity and severity markers compared with those of ins/ins genotype. • In RA patients, the del allele was significantly associated with higher IL-6 levels in a dose-dependent manner. • IL-6 plasma levels are independently associated with an increased risk of presenting erosive arthritis. • The NFKB1 -94ins/delATTG polymorphism contributes to the severity and progression of RA through IL-6 levels modulation in Egyptian patients.
类风湿关节炎（RA）是一种炎症性自身免疫性疾病，可导致进行性和功能性残疾。先前的数据表明，RA 患者的一些炎症细胞因子失调。已经在不同的 RA 人群中研究了 NFKB1 基因的多态性。具体研究表明，NFKB1 启动子-94ins/delATTG（rs28362491）多态性似乎与 IL-6 表达的改变相关，可能导致疾病的发展。我们旨在评估 NFKB1-94ins/delATTG 多态性与埃及患者 RA 严重程度的生化和临床标志物之间的关系。
研究对象包括来自埃及人群的 196 名 RA 患者。使用 TaqMan 测定法通过实时 PCR 对 NFKB1-94ins/delATTG 多态性进行基因分型。使用 ELISA 法评估血浆 IL-6 浓度。
侵蚀性关节炎病例中（del/del+ins/del）基因型的频率明显高于非侵蚀性关节炎病例（63.0% vs. 47.7%，OR=1.86，95%CI：1.05-3.30，p：0.043）。与 ins/ins 基因型相比，携带 del 等位基因的患者具有更高的活动和严重程度标志物。del 等位基因与剂量依赖性更高的 IL-6 水平显著相关。与 ins/ins 基因型（11.4±4.21pg/ml）相比，del/del（41.4±16.2pg/ml）和 ins/del（19.1±12.4pg/ml）基因型的患者血浆 IL-6 水平明显更高。在包括与更高 IL-6 水平相关的混杂因素（RF、疾病持续时间和 DAS28）的多元方差分析中，NFKB1-94ins/delATTG 多态性保留了其作用。逻辑回归分析显示，高 IL-6 血浆水平与侵蚀性 RA 发病风险增加独立相关，而 NFKB1-94ins/delATTG 多态性与侵蚀性关节炎的进展无直接关系。
我们的数据表明，NFKB1-94ins/delATTG 多态性通过调节埃及患者的 IL-6 水平，导致 RA 的严重程度和进展。关键点：•与 ins/ins 基因型相比，携带 del 等位基因的患者具有更高的活动和严重程度标志物。•在 RA 患者中，del 等位基因与剂量依赖性更高的 IL-6 水平显著相关。•IL-6 血浆水平与侵蚀性关节炎发病风险增加独立相关。•NFKB1-94ins/delATTG 多态性通过调节 IL-6 水平导致埃及患者 RA 的严重程度和进展。
