Genetic polymorphisms near IL-21 gene associated with Th17 cytokines confer risk for systemic lupus erythematosus in Chinese Han population

Abstract

Objective 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. Methods 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. Results 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. Conclusions 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.

Impact of Genetic Polymorphisms in the Interleukin-18 and Interleukin-21 Genes on the Risk and Clinical Outcomes of Multiple Sclerosis

“…These observations indicate that IL-21 may be involved in the progression of multiple autoimmune diseases (Liu et al, 2015). Several pieces of literature have investigated the possible association between IL-21 SNPs and various autoimmune disorders, including MS, SLE, and RA (Gharibi et al, 2015, Meng et al, 2019, Ali et al, 2022, Carreño-Saavedra et al, 2023, revealing that IL-21 is a potential locus for autoimmune diseases.…”

Association of TNFSF4 rs1234315, rs2205960 polymorphisms and systemic lupus erythematosus susceptibility: a meta-analysis

“…2 In particular, many studies have shown that genetic loci are associated with SLE susceptibility. 3…”

Analysis of the frequency of single nucleotide polymorphisms in cytokine genes in patients with New Onset Diabetes After Transplant

“…Understanding such pleiotropic effects of IL-6 in in the pathogenesis of the disease may help determine the progression, severity and duration of the disease. IL-6 is currently considered an important target for clinical interventions 28,29 . Hence, better understanding of IL-6 role in the pathogenesis of NODAT can provide rational and therapeutic intervention 29 .…”

“…IL-6 is currently considered an important target for clinical interventions 28,29 . Hence, better understanding of IL-6 role in the pathogenesis of NODAT can provide rational and therapeutic intervention 29 . The guanine (G)/cytosine (C) polymorphism in the IL-6 proximal promoter region, at position IL-6 G (− 174) C, regulates transcription of the IL-6 gene and subsequently in IL-6 levels of plasma and serum 19,30 ; the same polymorphism was found to be associated with fasting insulin levels,insulin sensitivity, and the integrated area under the curve of serum glucose concentrations 30,31 .…”