The association between IL-1 family gene polymorphisms and colorectal cancer: A meta-analysis

Highlights

• Associations between IL-1 family gene polymorphisms and risk of CRC were studied.

• IL-1a 3783553, IL-1β+31 C/T, +51C/T and IL-1RN RNVR are critical genes for CRC.

• IL-1B +511 C/T and IL-1RN+ 2018T/C were associated with CRC in Asian.

• More evidences were provided for the role of IL-1faminly gene polymorphisms on CRC.

Abstract

Background

Colorectal cancer (CRC) is a major public health problem given its high incidence and mortality. This study focuses on examining the associations between IL-1α, IL-1β, and IL-1RN polymorphisms and colorectal cancer susceptibility.

Methods

A systematic literature search of PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure) and Wan Fang databases was conducted to identify relevant studies. Relevant data were extracted from the original included studies. The correlation was demonstrated based on the odds ratio (OR) and corresponding 95% confidence intervals (95% CIs). Publication bias was investigated by Egger's line regression test and Begg's funnel plot.

Results

Eighteen independent studies involving 6218 cases and 10160 controls were eligible for this pooled analysis. Overall, the result revealed that the IL-1α rs3783553 polymorphism was significantly associated with an increased risk of CRC (G vs. C, OR = 1.02, 95% CI = 0.90–1.15, I² = 51%, P = 0.78; GG vs. CC, OR = 1.97, 95% CI = 1.04–3.74, I² = 70%, P = 0.04; GC vs. CC, OR = 1.75, 95% CI = 1.12–2.75, I² = 42%, P = 0.01; GG + GC vs. CC, OR = 1.85, 95% CI = 1.08–3.18, I² = 63%, P = 0.03; and GG vs. GC + CC, OR = 1.28, 95% CI = 1.04–1.58, I² = 39%, P = 0.02), and significance was also noted for IL-1RN VNTR under the dominant model (22 + 2L vs. LL, OR = 1.49, 95% CI = 1.01–2.19, I² = 77%, P = 0.045) and allelic contrast model (2 vs. L, OR = 1.28, 95% CI = 1.00–1.64, I² = 58.6%, P = 0.047). For IL-1β + 31C/T, significance was observed in the dominant model (CC + CT vs. TT, OR = 0.83, 95% CI = 0.69–0.99, I² = 52%, P = 0.034) and the heterozygous model (CT vs. TT, OR = 0.80, 95% CI = 0.65–0.98, I² = 60%, P = 0.04). For IL-1β + 511 C/T, a significant association was noted in four gene models (CT vs. TT, OR = 0.72, 95% CI = 0.63–0.83, I² = 0%, P < 0.001; CC + CT vs. TT, OR = 0.74, 95% CI = 0.65–0.84, I² = 0%, P < 0.001; CC vs. TT, OR = 0.77, 95% CI = 0.65–0.91, I² = 30.9%, P = 0.003; C vs. T, OR = 0.87, 95% CI = 0.80–0.95, I² = 38%, P = 0.001), but a significant relationship was not found in the recessive model (CC vs. CT + TT, OR = 1.09, 95% CI = 0.86–1.38, I² = 57.1%, P = 0.25). In addition, borderline statistical significance was noted between IL-1β + 3954 Ins/Del and CRC in the homozygous model, but no significance was identified for IL-1β + 3737 G/A, Il-1β + 1464 G/C, and IL-1RN + 2018 T/C under all five genetic models. In the subgroup analysis of ethnic groups, significant associations with CRC were found for IL-1β + 31 (CC vs. TT: OR = 0.82, 95% CI = 0.67–0.99, I² = 20.2%, P = 0.04; CT vs. TT: OR = 0.62, 95% CI = 0.47–0.82, I² = 0%, P < 0.001; CC + CT vs. TT: OR = 0.69, 95% CI = 0.55–0.87, I² = 29.7%, P = 0.001), IL-1β + 511 (CT vs. TT, OR = 0.65, 95% CI = 0.55–0.77, I² = 0%, P < 0.001; CC + CT vs. TT, OR = 0.67, 95% CI = 0.58–0.78, I² = 0%, P < 0.001; C vs. T, OR = 0.83, 95% CI = 0.75–0.92, I² = 49.6%, P < 0.001) and IL-1RN + 2018 T/C in the allelic contrast model (T vs. C, OR = 0.66, 95% CI = 0.44–0.98, I² = 0%, P = 0.04) among Asians but not in Caucasians. A significant association between IL-1β + 1464 G/C polymorphisms in Caucasians was observed under the recessive model (OR = 0.87, 95% CI = 0.77–0.98, I² = 45%, P = 0.03).

Conclusion

The current meta-analysis demonstrated that IL-1α rs3783553, IL-1β + 31C/T, IL-1β + 511C/T, and IL-1RN VNTR are critical genes for CRC susceptibility.

Introduction

Colorectal cancer (CRC) represents a high proportion of cancer-related mortality and morbidity throughout the world. Recent epidemiology data revealed that approximately 1.8 million new cases were identified in 2018 worldwide, and CRC currently ranks as the third most common cause of cancer-related deaths (Bray et al., 2018). Moreover, it was estimated that 975,396 new cancer cases occurred among young adults worldwide in 2012, indicating that patients are increasingly younger (Fidler et al., 2017). Colorectal cancer is a serious health problem in the world as it is a major cause of mortality. The 5-year survival rate is <12% (Geng et al., 2017). Thus, actions should be taken to deal with this malignant tumor due to the rapid increase in the incidence and mortality of colorectal cancer (Hu et al., 2015). Unfortunately, the exact pathology and ethology of CRC remains unknown, but accumulating evidence suggests that genetic and environmental factors are associated with colorectal cancer. Numerous studies have demonstrated that single nucleotide polymorphisms (SNPs) plays a central role in the onset and development of CRC (Gulubova et al., 2018, Hu et al., 2012, Jafari-Nedooshan et al., 2019, Zhou and Bai, 2019).

Interleukin (IL)-1 has emerged as an indispensable member of the cytokine family, which is involved in innate inflammation and acquired immunity with new, unexpected vistas (Dinarello, 2018). The IL-1 gene family, including IL1α, IL1β and IL1RN, is located on chromosome 2q14, and these three related genes encode IL-1 alpha (IL-1α) protein, IL-1 beta (IL-1β) protein and IL-1 receptor antagonist (IL-1 Ra) protein, respectively (Voronov and Apte, 2015). In recent years, researchers have found that IL-1 acts at different levels in tumor initiation and progression and drives chronic inflammation, tumor angiogenesis, invasion and metastasis (Malik and Kanneganti, 2018, Mantovani et al., 2018). IL-1α and IL-1β, the two major IL-1 agonistic molecules, are pro-inflammatory cytokines involved in tumorigenesis (Grigaitis et al., 2019). IL-1α serves as a pleiotropic cytokine in human cancer progression, inflammatory responses and various immune activities, and secreted IL-1α is an active form that induces the tissue damage and tumor growth together with other regulatory factors (Kasza, 2013). IL-1α is generally accepted to be involved in the malignant process in CRC, including colon homeostasis, inflammation, carcinogenesis, and invasion (Voronov and Apte, 2015). Using a mouse model of colitis-associated cancer, Wang Y confirmed that infiltrating neutrophils secrete IL-1β, which promotes tumorigenesis by inducing IL-6 production by intestinal mononuclear phagocytes (Wang et al., 2014). In contrast, IL-1Ra as a natural endogenous biologic antagonist of the IL-1 receptor, can prevent downstream signaling in the presence of its agonists IL-1α and IL-1β (Kurzrock et al., 2019).

Recently, numerous studies on human polymorphisms in IL-1α, IL-1β, and IL-1RN have been performed, revealing that these polymorphisms are linked to the risk of colorectal cancer (Abbasian et al., 2018, Burada et al., 2013, Viet et al., 2005, Wang et al., 2015). However, controversial results have been obtained. Some studies found that the IL-1 gene was associated with an increased risk of CRC, whereas several studies indicated no obvious associations between the IL-1 gene and CRC. Due to a range of factors, such as the small number of subjects in a single study and gene-environment interactions, whether IL-1 family gene polymorphisms are related to CRC risk remains unclear to date. Meta-analysis could enhance the statistical power and allow more reliable conclusions to be drawn compared with a single study (Stroup et al., 2000). Hence, the present meta-analysis was conducted to further assess the effects of eight single nucleotide polymorphisms, namely, IL-1α (rs 3783553), IL-1β (+31C/T, +3954Ins/Del, +511C/T, +1464C/T, +3737G/A) and IL-1Ra gene variants (VNTR, +2018 T/C), on colorectal cancer.