Abdolahi Farzan, Dabbaghmanesh Mohammad Hossein, Haghshenas Mohammad Reza, Ghaderi Abbas, Erfani Nasrollah
Cancer Immunology Group, Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
Endocrine. 2015 Dec;50(3):698-707. doi: 10.1007/s12020-015-0623-9. Epub 2015 Jun 4.
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.
甲状腺癌是内分泌系统最常见的恶性肿瘤，遗传因素已被证明与其发病风险相关。白细胞介素-18（IL-18）是一种多效性促炎细胞因子，可诱导γ干扰素的产生，并参与1型辅助性T细胞的发育。为确定IL-18基因在甲状腺癌易感性中的作用，我们进行了一项病例对照研究，对105例甲状腺癌患者和148名来自伊朗人群的健康对照者的IL-18基因中的五个单核苷酸多态性（SNP）进行基因分型（启动子区域的-656 G/T（rs1946519）、-607 C/A（rs1946518）和-137 G/C（rs187238）以及5'非翻译区的+113 T/G（rs360718）和+127 C/T（rs360717））。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和等位基因特异性引物PCR进行基因分型。分析了不同基因型与甲状腺癌、肿瘤类型及肿瘤分期的相关性。将所有患者群体与对照组进行比较，发现-656 G/T位点的TT基因型与甲状腺癌风险显著增加相关[105例中有31例（30.1%），148例中有19例（13.1%），p = 0.002，比值比2.90，可信区间1.40 - 5.70]。在其他位点（-607 C/A、-137 G/C、+113 T/G和+127 C/T）未发现与甲状腺癌相关。排除髓样癌患者，仅纳入滤泡上皮来源的甲状腺癌患者，关于-656 G/T位点的基因型观察到几乎相同的结果。此外，在+127 C/T位点遗传纯合子基因型（CC）时，观察到滤泡上皮来源的甲状腺癌风险显著降低（患者组和对照组分别为94例中有40例（42.5%）和148例中有84例（56.8%），比值比0.56，比值比的95%可信区间0.32 - 0.98，p = 0.04）。单倍型分析表明，在32种可能的单倍型中患者的TAGTT单倍型频率显著高于对照组[188例中有12例（6.4%），292例中有2例（0.7%），p = 0.0008]，且这种差异经Bonferroni校正（n = 19）后仍具有统计学意义，显著性水平设定为0.003。排除髓样癌患者后观察到几乎相同的结果。未发现SNP与肿瘤分期之间存在关联。我们的结果表明，IL-18基因启动子-656 G/T位点为TT基因型的个体对甲状腺癌的易感性增加，以及IL-18基因中五个研究的SNP所形成的TAGTT单倍型。数据还表明，+127 CC基因型的遗传可能使个体免受滤泡上皮来源的甲状腺癌的侵害。
