A gene-disease association study of IL18 in thyroid cancer: genotype and haplotype analyses

Thyroid cancer is the most common malignancy of the endocrine system, and genetic factors have been shown to be associated with its risk. Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine that induces IFN-γ production and is involved in T helper type 1 development. To determine the role of IL-18 gene in thyroid cancer susceptibility, we conducted a case-control study, and genotyped five single nucleotide polymorphisms (SNPs) in IL-18 gene (-656 G/T (rs1946519), -607 C/A (rs1946518), and -137 G/C (rs187238) in the promoter region and +113 T/G (rs360718) and +127 C/T (rs360717) in 5'-untranslated region) in 105 patients with thyroid cancer and 148 healthy controls from Iranian population. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific primer-PCR were used for genotyping. The association of different genotypes with thyroid cancer, tumor type, and the tumor stage was analyzed. Comparing all of the patient population with the controls, TT genotype at position -656 G/T was observed to be associated with a significantly increased risk of thyroid cancer [31/105 (30.1 %) vs 19/148 (13.1 %), p = 0.002, OR 2.90, CI 1.40-5.70]. No association with thyroid cancer was found at other positions (-607 C/A, -137 G/C, +113 T/G, and +127 C/T). Excluding the patients with medullary carcinoma, and including only the ones with thyroid cancer derived from the follicular epithelium, nearly the same results were observed regarding the genotypes at position -656 G/T. Furthermore, significantly decreased risk of thyroid cancer derived from the follicular epithelium was observed upon inheritance of the homozygote genotype (CC) at position +127 C/T (40/94 (42.5 %) versus 84/148 (56.8 %) in patients and controls, respectively (OR 0.56, 95 % CI for OR 0.32-0.98, p = 0.04). Haplotype analysis indicated that among 32 possible haplotypes, TAGTT haplotype frequency was significantly higher in patients than in controls [12/188 (6.4 %) vs 2/292 (0.7 %), p = 0.0008] and this difference resisted Bonferroni correction (n = 19) and significant level set at 0.003. Nearly the same results were observed after excluding the patients with medullary carcinoma. No association was found between the SNPs and the stage of tumor. Our results suggest the increased susceptibility to thyroid cancer in subjects with TT genotype at position -656 G/T of the promoter of IL-18 gene, as well as TAGTT haplotype emerged from five studied SNPs in IL-18 gene. The data also suggest that the inheritance of +127 CC genotype may protect individuals from thyroid cancer derived from follicular epithelium.