Background and Purpose: Genetic polymorphisms of the interleukin-1β (IL-1β) promoter region (−511) and exon 5 +3954 and a variable number of tandem repeats in the IL receptor antagonist (IL-1RA) gene have been proposed as markers for calcium oxalate urolithiasis. Because the prevalence of these polymorphisms could be influenced by racial variation/ethnicity, we explored the association of IL-1 gene-cluster polymorphisms with stone formation in a north India population.
Patients and Methods: The case-control study involved 150 stone-free control subjects (mean age 46.5 ± 10.5 years) and 130 patients (mean age 40.0 ± 11.5 years) with calcium oxalate urolithiasis. Biallelic polymorphisms of two loci, IL-1β (−511) and IL-1β (+3954), as well as the penta-allelic variable number of tandem repeats of IL-1RA, were genotyped by polymerase chain reaction-based restriction analysis. Haplotypes were constructed for the IL-1 gene cluster using SNP Analyzer software.
Results: We observed a significant association between stone disease and IL-1β −511 and IL-1RA polymorphisms (P < 0.001 and P = 0.039, respectively), whereas no association was observed for IL-1β +3954 (P = 0.408). The frequency of the TT (−511) and I/II (410/240; IL-1RA) genotypes was higher in patients than in control subjects (50/130 v 16/150 and 55/130 v 38/150, respectively), whereas the frequencies of the haplotypes were similar (P = 0.485). Significant linkage disequilibrium showed that three genes were strongly linked (P < 0.0001). Patients with a combination of high IL-1β (−511 and +3954) and low IL-1RA genotypes were at significantly higher risk for urolithiasis (P < 0.001; odds ratio = 5.448, 0.013, and 2.560, respectively).
Conclusion: Our study demonstrated a strong association of IL-1RA and IL-1β-511 and suggested that differences in the IL-1 gene cluster could be linked to the risk of urolithiasis. A combination of IL-1β and IL-1RA associations exhibiting gene–gene interaction further substantiates the finding of risk.
