Interleukin-1β and receptor antagonist (IL-1Ra) gene polymorphisms and the prediction of the risk of end-stage renal disease

Cytokines play an important role in the pathogenesis of kidney disease and its progression to end-stage renal disease (ESRD). Inflammation is regulated by the genes of the interleukin 1 (IL-1) gene cluster. Therefore, it was hypothesized that a polymorphism in this gene cluster may be associated with the risk of ESRD. Polymorphisms in the IL-1 gene cluster were examined in a cohort of 222 ESRD patients and 206 controls of similar ethnicity. These individuals were genotyped for IL-1 P (promoter -511 and exon-5 +3953) genes and a variable number of tandem repeats (VNTR) in the IL-1 receptor antagonist gene (IL-IRa). There was significant difference in genotype frequencies between ESRD patients and control group for ILAP (promoter region and exon-5) and IL-1Ra gene polymorphism (p < 0.001, 0.006 and < 0.001, respectively). A significant difference was observed in IL-IRa for 1/1 (410/410) and 1/2 (410/ 240) genotypes, and the risk for ESRD was higher in those carrying the 1/1 genotype (p=0.014, OR=1.692, and p < 0.001, OR=0.163). Also identified was a novel, rare allele of a single copy of 86 bp in ESRD patients as compared with the controls. The haplotype 'T-E2-1' frequency distribution between patients and controls revealed greater than threefold risk (p=0.001, OR = 3.572, 95% CI = 1.589-8.032). Genetic linkage between the IL-I beta promoter region and exon-5 and between the ILAP promoter and IL-1Ra of IL-I gene demonstrated a strong association among the variants in controls (D' = 0.42, p < 0.001, and D' = 0.39, p = 0.001). Thus, the three polymorphisms within the IL-1 cluster are associated with ESRD. This finding is perhaps one of the strongest associations between genotype and ESRD reported, and it suggests that the IL-I gene cluster affects the risk of development of ESRD.