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

Abstract

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.