Interleukin-1beta 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 beta (promoter -511 and exon-5 +3953) genes and a variable number of tandem repeats (VNTR) in the IL-1 receptor antagonist gene (IL-1Ra). There was significant difference in genotype frequencies between ESRD patients and control group for IL-1beta (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-1Ra 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-1beta promoter region and exon-5 and between the IL-1beta promoter and IL-1Ra of IL-1 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-1 gene cluster affects the risk of development of ESRD.
Manchanda
P K
PK
Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
Kumar
A
A
Bid
H K
HK
Mittal
R D
RD
D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000235:genetics*; D015810:Linkage Disequilibrium; D018598:Minisatellite Repeats; D005810:Multigene Family; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D012795:Sialoglycoproteins / Q000235:genetics*
D017931:DNA Primers; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins