Interaction analysis of IL-12A and IL-12B polymorphisms with the risk of colorectal cancer

Abstract

IL-12 is an antitumor cytokine with functions of inhibiting tumor growth, invasion, and metastasis, indicating that IL-12 is a promising candidate for cancer treatment. The aim of this study was to investigate the association of IL-12A rs568408, IL-12A rs2243115, and IL-12B rs3212227 with the susceptibility to colorectal cancer (CRC). Two hundred and fifty-seven histopathologically confirmed CRC patients and 236 age- and gender-matched controls were enrolled. The three polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. We found that the IL-12A rs568408 AG/AA genotypes were associated with an increased risk of CRC with an adjusted odds ratio (OR) of 1.66 (95 % confidence interval (CI), 1.11-2.48). Stratified analyses showed that patients carrying the IL-12B rs3212227AC/CC genotypes had a 1.97-fold increased risk of tumor metastasis (OR = 1.97; 95 % CI, 1.04-3.70). Gene-gene interaction analysis showed that subjects carrying the IL-12A rs568408AG/AA and IL-12B rs3212227AA genotypes had a 2.40-fold increased risk of CRC (OR = 2.40; 95 % CI, 1.14-5.07) and individuals carrying the IL-12A rs568408AG/AA and IL-12B rs3212227AC/CC genotypes had a 1.93-fold increased risk of CRC (OR = 1.93; 95 % CI, 1.10-3.41). These findings indicate that IL-12A rs568408 and IL-12B rs3212227 may be related to the development of CRC.

Role of interleukin-12 gene polymorphisms in the onset risk of cancer: a meta-analysis

“…However, no significant association was found after excluding one study [20] not according to the HWE (All P > 0.05, Figure 2). In stratified analysis by ethnicity, we observed an increased risk of overall cancers among Caucasians (recessive model: OR = 2.63, 95% CI = 1.05-6.56; homozygote model: OR = 2.46, 5% CI = 1.20-5.06; allele model: OR = 1.19, 95% CI = 1.05-1.35).…”

“…The eligible studies involved several different cancer types including hepatocellular, colorectal, gastric, cervical, breast, prostate, osteosarcoma, esophageal, brain, cervical, ovarian, nasopharyngeal, lung, Non-Hodgkin lymphoma, and cutaneous malignant melanoma. Every study was in according with HWE except for two [20, 28]. The main characteristics of the included studies are presented in Table 1.…”

“…Unfortunately, the functional role on cancer risk that IL-12 gene polymorphisms played was still uncertain. For instance, a study performed by Sun et al found that IL-12A rs568408 may increase the susceptibility on colorectal cancer [20], being contrary to the conclusion of the study by Huang et al which suggested IL-12A rs568408 was not associated with colorectal cancer[21]. And, a previous study reported that the loci of rs3212227 in IL-12B gene definitely contributed to increasing cervical cancer risk in Chinese population [25].…”

“…Because of these pleiotropic activities of IL-12, dozens of molecular epidemiologic studies have explored the influences of IL-12 polymorphisms on susceptibility of various cancers, including hepatocellular carcinoma [14–19], colorectal cancer [13, 20, 21] and gastric cancer [22–24], etc. The most commonly fascinating loci were rs3212227 in IL-12B gene, rs568408 and rs2243115 in IL-12A genes, perhaps owing to their function to influence IL-12 gene expression, reduce protein synthesis, and subsequently result in cancer.…”

Polymorphisms of T helper cell cytokine-associated genes and survival of hemodialysis patients – a prospective study

“…In the study by Mishra et al [17], IL-12 correlated with endothelial dysfunction, insulin resistance and pro-inflammatory markers in type 2 diabetes patients. The minor allele in IL12A rs568408 has been associated with numerous neoplasms such as hepatocellular carcinoma [18], cervical cancer [19], colorectal cancer [20] or osteosarcoma [21]. IL12A rs568408 seems to be associated with autoimmune disorders: the A allele in IL12A rs568408 was found to be significantly higher in patients with Graves’ disease than in controls [22].…”