Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population

Abstract

IL-12 and IL-18 are immunomodulatory cytokines that play important roles in host immune response against cancers. Variation in DNA sequence in gene promoter may lead to altered IL-18 production and/or activity, and hence can modulate an individual's susceptibility to BC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter −137 G/C and −607C/A polymorphisms and IL12 (−16974) A/C with the risk of BC in North Indian population. Polymorphisms in IL-18 and IL-12 genes were analyzed in 200 BC patients and 200 age, ethnicity and sex-matched controls, using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) and amplification refractory mutation specific-polymerase chain reaction (ARMS) method. The concentrations of IL-18 in serum were determined by ELISA. Significant association was observed with IL18 (−137) G/C heterozygous genotype (GC) with 1.96 folds risk of BC as well at C allele carrier and variant C allele having 2 fold and 1.6 fold risk for BC respectively. IL18 (−607) C/A, heterozygous CA genotype also showed a high risk (OR=1.59) for BC. While IL12 (−16974) A/C heterozygote genotype and C allele carrier demonstrated reduced risk of BC. Hetero genotype of IL18 (−137) G/C was associated with risk of recurrence (HR=2.35) in superficial BC patients receiving BCG treatment thus showing least survival. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls. Serum IL-18 levels were significantly higher in BC patients than in the healthy subjects (p=0.025). Serum IL-18 levels was also significantly associated with IL18 (−137) G/C in heterozygous genotype (GC) (p=0.048). Our results suggest that IL-18 gene polymorphism contributes to bladder cancer risk whereas IL-12 is protective. A relation between IL18 (−137) G/C in heterozygous genotype with elevated IL-18 serum level and bladder cancer risk has been registered in the present study.