Meng Yanming, Xu Heng, Zhang Shouyue, Zhang Junlong, Wang Lu, Tang Honghu, Wu Yongkang
1 Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
2 Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, China.
Lupus. 2019 Mar;28(3):406-413. doi: 10.1177/0961203319829821. Epub 2019 Feb 18.
Interleukin-21 (IL-21) contributes to expansion, differentiation, and modulation of various immunocompetent cells. Deregulated production of IL-21 plays a role of cardinal significance in the pathogenesis of systemic lupus erythematosus (SLE). We aimed to determine whether single nucleotide polymorphisms (SNP) near the IL-21 gene have significant association with SLE susceptibility and the T helper-related inflammatory cytokine profile of SLE patients.
We enrolled 460 SLE patients and 460 healthy controls. Whole genome analysis was used to investigate different genes including IL-21. Loci rs11725913, rs11937669, rs7676539, rs111438679, rs115935829, rs373549, rs4487356, and rs79923870 were further genotyped using an improved multiplex ligation detection reaction technique. Susceptibility, levels of Th-related inflammatory cytokines, and some clinical indexes of SLE patients were analyzed.
rs11725913 and rs11937669 were identified for association with SLE in Chinese Han Population. The allelic frequency of rs11725913 approached significance (odds ratio (OR) (95% Confidence Interval (CI)) = 1.431 (1.122-1.825), P = 0.004). GT genotype at rs11725913 and GA genotype at rs11937669 were associated with SLE susceptibility (OR (95% CI) = 1.448 (1.074-1.952), P = 0.015; OR (95%CI) = 1.356 (1.013-1.815), P = 0.040, respectively). Dominant model analysis provided us with further validation (rs11725913: OR (95%CI) = 1.502 (1.126-2.004), P = 0.006; rs11937669: OR (95%CI) = 1.356 (1.025-1.793), P = 0.033). Cases with rs11937669 risk GA-genotype had higher serum IL-6 concentration than others ( P = 0.022). Dominant model analysis showed that patients with the wild type (AA-genotype) at rs11937669 had significantly lower soluble CD40 ligand ( P = 0.029) but higher IL-17A ( P = 0.040) compared with others. Cases carrying rs11725913 T allele had higher gamma glutamyl transpeptidase level ( P = 0.045) than those without.
We identified two new loci, rs11725913 and rs11937669, associated with SLE risk in Chinese Han population. This research provided a new insight into the significant relationship between polymorphisms upstream IL-21 and Th17 inflammatory response, which suggest that the sequence upstream of the IL-21 gene is an important region involved in the Th17-related pathway.
白细胞介素-21（IL-21）有助于多种免疫活性细胞的扩增、分化和调节。IL-21的失控产生在系统性红斑狼疮（SLE）的发病机制中起关键作用。我们旨在确定IL-21基因附近的单核苷酸多态性（SNP）是否与SLE易感性以及SLE患者的辅助性T细胞相关炎性细胞因子谱存在显著关联。
我们纳入了460例SLE患者和460例健康对照。采用全基因组分析来研究包括IL-21在内的不同基因。使用改进的多重连接检测反应技术对rs11725913、rs11937669、rs7676539、rs111438679、rs115935829、rs373549、rs4487356和rs79923870位点进行进一步基因分型。分析SLE患者的易感性、Th相关炎性细胞因子水平和一些临床指标。
在中国汉族人群中，rs11725913和rs11937669被确定与SLE相关。rs11725913的等位基因频率接近显著水平（优势比（OR）（95%置信区间（CI））=1.431（1.122 - 1.825），P = 0.004）。rs11725913的GT基因型和rs11937669的GA基因型与SLE易感性相关（OR（95%CI）=1.448（1.074 - 1.952），P = 0.015；OR（95%CI）=1.356（1.013 - 1.815），P = 0.040）。显性模型分析为我们提供了进一步验证（rs11725913：OR（95%CI）=1.502（1.126 - 2.004），P = 0.006；rs11937669：OR（95%CI）=1.356（1.025 - 1.793），P = 0.033）。携带rs11937669风险GA基因型的患者血清IL-6浓度高于其他患者（P = 0.022）。显性模型分析显示，rs11937669野生型（AA基因型）患者的可溶性CD40配体显著更低（P = 0.029），但IL-17A更高（P = 0.040）。携带rs11725913 T等位基因的患者γ-谷氨酰转肽酶水平高于未携带者（P = 0.045）。
我们在中国汉族人群中鉴定出两个与SLE风险相关的新位点，rs11725913和rs11937669。本研究为IL-21上游多态性与Th17炎性反应之间的显著关系提供了新的见解，这表明IL-21基因上游序列是参与Th17相关途径的重要区域。
