Objective: The aetiology of systemic lupus erythematosus (SLE) is incompletely understood. Both genetic and environmental factors are implicated in the pathogenesis of the disease. Herein, we describe genetic association between SLE and polymorphisms in the interleukin (IL)-21 gene. The reported effect of IL-21 on B-cell differentiation into plasma cells and its effect on dendritic cell maturation and T-cell responses make IL-21 an attractive candidate gene for SLE. Methods: Three single nucleotide polymorphisms (SNPs) in the IL-21 gene were genotyped in a total of 2636 individuals (1318 cases and 1318 controls matched for age, sex and race). Population-based case-control association analyses were performed. Results: We found a genetic association with SLE and two SNPs located within the IL-21 gene (rs907715: x 2 = 11.55, p,0.001; rs2221903: x 2 = 5.49, p = 0.019). Furthermore, genotypes homozygous for the risk alleles were more frequent than genotypes homozygous for the non-risk alleles in European-American patients as compared to controls (rs907715 (GG versus AA): odds ratio (OR) = 1.66, p = 0.0049; rs2221903 (GG versus AA): OR = 1.60, p = 0.025). Conclusion: Our findings indicate that IL-21 polymorphism is a candidate association with SLE. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by the production of autoantibodies directed against a host of nuclear components. The disease is relapsing and affects multiple organ systems including the skin, kidneys, lungs, heart and the central nervous system. The aetiology of SLE is incompletely understood, but is likely multifactorial. Both genetic and environmental factors are thought to play a role in the pathogenesis of SLE. Familial aggregation of the disease, a higher reported concordance rate in monozygotic compared to dizygotic twins, and the multiple genetic linkages and associations discovered all suggest an important genetic component contributing to the aetiology of SLE.1 In addition, a large body of evidence accumulated over the past 20 or so years suggests a role for abnormal DNA methylation in the pathogenesis of drug-induced and idiopathic SLE.

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Increased expression of interferon (IFN)-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). One transcription factor responsible for regulating IFN, interferon regulatory factor-5 (IRF5), has been associated with SLE in genetic studies of Asian, Caucasian and Hispanic populations. We genotyped up to seven polymorphic loci in or near IRF5 in a total of 4870 African-American and Caucasian subjects (1829 SLE sporadic cases and 3041 controls) from two independent studies. Population-based case-control comparisons were performed using the Pearson's w 2 -test statistics and haplotypes were inferred using HaploView. We observed significant novel associations with the IRF5 variants rs2004640 and rs3807306 in African Americans and replicated previously reported associations in Caucasians. While we identified risk haplotypes, the majority of haplotypic effects were accounted for by one SNP (rs3807306) in conditional analyses. We conclude that genetic variants of IRF5 associate with SLE in multiple populations, providing evidence that IRF5 is likely to be a crucial component in SLE pathogenesis among multiple ethnic groups.

Systemic lupus erythematosus (SLE) is