Genetic variability at promoters of IL-18 (pro-) and IL-10 (anti-) inflammatory gene affects susceptibility and their circulating serum levels: An explorative study of prostate cancer patients in North Indian populations

Abstract

Inflammation is an important hallmark of all types of cancers with a well-established role in carcinogenesis. The net inflammatory response is determined by the balance between pro- and anti-inflammatory cytokines, the levels of which may be affected by the genetic make-up. Interleukin (IL)-18, a pro-inflammatory cytokine expressed by various cells including those of the prostate, is a key mediator of anti-cancer immune response. IL-10, an anti-inflammatory cytokine associated with tumour malignancy, causes escape from immune surveillance. This study hypothesizes that genetic variants of IL-18 (-607 C/A and -137 G/T) and IL-10 (-819 C/T and -592 C/A) may influence the circulating levels of these interleukins, thereby generating susceptibility risk to prostate cancer. The study was conducted on 676 subjects (controls and patients of prostate cancer (PCa): 291 each; and 94 patients with benign prostate hypertrophy (BPH)). Genotyping was performed by PCR-RFLP and Real-Time PCR probe-based method. Circulating interleukin levels were obtained by ELISA. Circulating IL-18 levels were significantly elevated in cancer and BPH patients carrying GG genotypes for -137 of IL-18. The trend of circulating IL-18 levels was GG>GC>CC, observed in all groups. The -137 genetic variants of IL-18 significantly associated with PCa risk were GC, CC, and GC+CC, compared to GG (OR: 1.71, 95% CI: 1.20-2.46; OR: 3.35, 95% CI: 2.03-5.53; and OR: 2.05, 95% CI: 1.46-2.87, respectively). A significant association of AA and CA+AA against CC genotype was observed at -607 locus of IL-18 (OR: 0.46, 95%CI: 0.29-0.72; OR: 0.61, 95% CI: 0.41-0.90, respectively). Significantly elevated levels of IL-10 were observed with TT (wild) genotype at -819 of IL-10, compared to the CC (homozygous mutant) genotype in all three groups of subjects. However, no significant association was found between IL-10 promoter genotypes and PCa risk. We conclude that genetic variants of IL-18 and IL-10 promoters influence the circulating levels of these interleukins. Variations at -137 and -607 loci of IL-18 are associated with susceptibility to PCa.

Keywords: Anti-inflammatory cytokine; Genetic polymorphism; Pro-inflammatory cytokine; Prostate carcinoma; Prostate carcinoma susceptibility.