Association of interleukin-1beta gene and receptor antagonist polymorphisms with calcium oxalate urolithiasis.
OBJECTIVE
Genetic polymorphisms of the interleukin-1beta (IL-1beta) 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.


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-1beta (-511) and IL-1beta (+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-1beta -511 and IL-1RA polymorphisms (P < 0.001 and P = 0.039, respectively), whereas no association was observed for IL-1beta +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-1beta (-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).


CONCLUSIONS
Our study demonstrated a strong association of IL-1RA and IL-1beta-511 and suggested that differences in the IL-1 gene cluster could be linked to the risk of urolithiasis. A combination of IL-1beta and IL-1RA associations exhibiting gene-gene interaction further substantiates the finding of risk.
Mittal
Rama D
RD
Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. ramamittal@yahoo.com
Bid
Hemant K
HK
Manchanda
Parmeet K
PK
Kapoor
Rakesh
R
D000328:Adult; D002129:Calcium Oxalate / Q000652:urine*; D004247:DNA / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood / Q000235:genetics*; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D052878:Urolithiasis / Q000097:blood / Q000235:genetics* / Q000652:urine
D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D002129:Calcium Oxalate; D004247:DNA