Interleukin-40 (IL-40) 是一种由 17 号染色体开放阅读框 99 (C17orf99) 基因编码的新型细胞因子。最近的研究表明，类风湿性关节炎 (RA) 患者的 IL-40 水平显着上调。然而，C17orf99 基因的遗传变异与 RA 风险之间的关联尚未得到研究。在这项病例对照研究中，首次对 120 名患有 RA 的伊拉克妇女（30 名新诊断的 [ND] 和 90 名药物治疗的 [MD；接受肿瘤治疗）中的两个基因间变异 rs2004339 A/G 和 rs2310998 G/A 进行了基因分型。坏死抑制剂依那西普加甲氨蝶呤]）和 110 名对照女性使用 TaqMan 5'-等位基因辨别方法。还使用酶联免疫吸附测定试剂盒测定血清 IL-40 水平。采用多项logistic回归分析对rs2004339和rs2310998在五种遗传模型（等位基因、隐性、显性、超显性和共显性）下进行分析。结果显示，rs2004339 的突变 A 等位基因（等位基因模型）和纯合 AA 基因型（共显性模型）与 RA 风险增加显着相关（比值比 [OR] 分别 = 3.37 和 7.44；校正概率 [pc] ] < 0.001），而 rs2310998 显示与 RA 风险无关。比较ND和MD患者的rs2004339和rs2310998的等位基因和基因型频率，没有统计学上的显着差异。两种变体（按rs2004339-rs2310998的顺序）的单倍型分析显示，单倍型A-A（OR = 1.72；pc = 0.024）和A-G（OR = 2.85；pc < 0.001）与RA风险增加相关。与对照组相比，RA 患者的 IL-40 水平（中位数和四分位数范围）显着升高（29.3 [15.5-41.5] vs. 12.6 [7.4-18.8] pg/mL；p < 0.001）。 IL-40水平不受病程或疾病活动度的影响，但rs2310998基因型有影响； AA 基因型女性的 IL-40 水平显着高于 GG 基因型女性（20.1 [12.9-37.1] vs. 15.8 [8.3-22.6] pg/mL；p = 0.006）。关于药物治疗，与 MD 病例相比，ND 病例中 IL-40 的水平往往升高，但没有显着差异。总之，突变 A 等位基因和基因间变异 rs2004339 的突变型 AA 基因型与伊拉克女性患 RA 的风险增加有关。患者（尤其是 ND 患者）的血清 IL-40 水平也升高，并且受到突变型 AA 基因型的积极影响。因此，IL-40 在 RA 发病机制中的作用已被指出。版权所有 © 2023 Elsevier Ltd。保留所有权利。

Interleukin-40 (IL-40) is a novel cytokine encoded by the chromosome 17 open reading frame 99 (C17orf99) gene. Recent studies have shown that IL-40 levels are significantly up-regulated in patients with rheumatoid arthritis (RA). However, the association of genetic variants of the C17orf99 gene with the risk of RA has not been investigated. In this case-control study, two intergenic variants, rs2004339 A/G and rs2310998 G/A, were genotyped for the first time in 120 Iraqi women with RA (30 newly diagnosed [ND] and 90 medicated [MD; treated with the tumor necrosis inhibitor etanercept plus methotrexate]) and 110 control women using TaqMan 5'-allele discrimination method. Serum IL-40 levels were also determined using an enzyme-linked immunosorbent assay kit. Multinomial logistic regression analysis was used to analyze rs2004339 and rs2310998 under five genetic models (allele, recessive, dominant, over-dominant, and co-dominant). Results revealed that the mutant A allele (allele model) and the homozygous AA genotype (co-dominant model) of rs2004339 were significantly associated with an increased risk of RA (odds ratio [OR] = 3.37 and 7.44, respectively; corrected probability [pc] < 0.001), while rs2310998 showed no association with RA risk. When comparing the allele and genotype frequencies of rs2004339 and rs2310998 between ND and MD patients, there were no statistically significant differences. Haplotype analysis of the two variants (in the order rs2004339-rs2310998) revealed that haplotypes A-A (OR = 1.72; pc = 0.024) and A-G (OR = 2.85; pc < 0.001) were associated with an increased risk of RA. IL-40 levels (median and interquartile range) were significantly elevated in RA patients compared to controls (29.3 [15.5-41.5] vs. 12.6 [7.4-18.8] pg/mL; p < 0.001). IL-40 levels were not influence by disease duration or disease activity, but the rs2310998 genotypes had an effect; IL-40 levels were significantly higher in women with the AA genotype than in women with the GG genotype (20.1 [12.9-37.1] vs. 15.8 [8.3-22.6] pg/mL; p = 0.006). Regarding medication, IL-40 tended to show elevated levels in ND cases compared to MD cases but without a significant difference. In conclusion, the mutant A allele and the mutant-type AA genotype of the intergenic variant rs2004339 were associated with an increased risk of RA among Iraqi women. Serum IL-40 levels were also elevated in patients, particularly ND patients, and were positively affected by the mutant-type AA genotype. Accordingly, the role of IL-40 in the pathogenesis of RA has been indicated.Copyright © 2023 Elsevier Ltd. All rights reserved.