The Health Outcome
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology in which damage is mediated by autoantibodies and immune complexes. SLE is more common in women than men (90% of cases are women), and more common in African Americans than in whites.
The Finding
The primary goal of this study was to examine association between SLE and five alleles in the interleukin 1 gene cluster in the interleukin 1-alpha, interleukin 1-beta, and interleukin 1 receptor antagonist genes. This study was a case-control study with population-based controls from North Carolina and South Carolina . Cases (n=265) and controls (n=355) were frequency-matched for age, sex (90% female), and state of residence. Controls were identified through state driver's license records, and were excluded if they had ever been diagnosed with any kind of lupus. 60% of cases and 30% of controls were African American. Polymorphisms at five loci were examined: IL1
-889(C-->T), IL1 +4845(C-->T), IL1ß-511 (C-->T), IL1ß +3953(G-->T), and IL1Ra (86 bp VNTR). The IL1A -889 (C/C) genotype was associated with lupus in African Americans (OR = 3.1, 95% CI 1.5 to 6.1, p=0.001) and in whites (OR = 2.9, 95% CI 1.4 to 6.0, p=0.005). The IL1B -511 T allele was associated with SLE in African Americans (OR = 2.1, 95% CI 1.1 to 4.2). Allele 3 of IL1Ra was inversely associated with SLE in African Americans (OR = 0.1, 95% CI 0.0 to 0.7). Population attributable risk percent (PARP) for IL1A -889 (C/C) genotype was 34% for African Americans and 39% for whites; ARP for the IL1B -511 T allele was 44% for African Americans. There was interaction between IL1A -889 and IL1B -511 for risk of proteinuria (p=0.002). The authors concluded that two IL1 gene promoter regions were significantly associated with SLE in this study sample, supporting the hypothesis that altered or imbalanced IL1 production may affect the risk of developing SLE.
Public Health Implications
The results of this study are compelling because they support the hypothesis that variation in expression of gene products from the IL-1 gene cluster is involved in the pathogenesis of SLE. Because differences in expression of IL-1 have been observed in SLE, it is plausible that the alleles observed to be associated with SLE in this study play a role in the etiology of SLE by affecting the expression of IL-1alpha and IL-1beta, rather than reflecting linkage disequilibrium. Investigations into the relationship of these alleles with IL-1 production will provide more evidence about this gene-disease association. Disturbances in this biological pathway may be amenable to pharmacological intervention. Furthermore, knowledge of these associations may help in the elucidation of controllable environmental risk factors for lupus.
References
Parks C, Cooper G, Dooley M, Treadwell E, St. Clair E, Gilkeson G, Pandey J. Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States . Ann Rheum Dis. 2004;63:91-94.
