2q13

DIRA,ICIL-1RA,IL-1RN,IL-1ra,IL-1ra3,IL1F3,IL1RA,IRAP,MVCD4

Various cancers

The IL1 cluster has been strongly associated with different types of cancer. Multiple studies have shown that IL1RN, included in this cluster is altered in cancer development. IL1RN plays a central role in the response to pathogens associated with cancer etiopathogenesis (Roberge et al., 1996; Hurme and Helminen, 1998; Wang et al., 2003; Queiroz et al., 2004; Rocha et al., 2005) and chronic inflammation, well described as an important risk factor in cancer development (Hanahan and Weinberg, 2011; Baniyash et al., 2014; Khatami, 2014), thus, cytokines such as IL1RN could be used as risk and progression markers in the future.
In the meta-analysis performed by Zhang and cols., which included 71 studies of multiple cancers, with 14854 cases and 19337 controls, the research group found a consistent association with gastric cancer. IL1RN polymorphisms frequency is significantly different across ethnicities; the frequency of allele 2 is significantly lower in Asian controls (11.14%) compared to Caucasian controls (26%) (Zhang et al., 2011).

Gastric cancer

Gastric cancer after H. pylori infection susceptibility has been linked with IL1RN gene. Studies of genetic association have shown an increased risk of gastric cancer with the allele IL1RN*2 across different populations (El-Omar et al., 2000; Furuta et al., 2002; Alpizar-Alpizar et al., 2005; Garza-Gonzalez et al., 2005; Palli et al., 2005; Morgan et al., 2006; Oliveira et al., 2012). However, IL1RN*2 has been also been associated independently of H. pylori infection (Mattar et al., 2013).

The inflammatory response after H. pylori infection has been linked to the IL1 gene cluster. The infection induces the synthesis of IL1B which binds to its target receptor and starts the inflammatory response against the pathogen (Sierra et al., 2008). The IL1RN competitively binds to the IL1 receptor with the same affinity as IL1 without activating the inflammation cascade, modulating the effects of IL1B. The severity of damage caused by inflammatory response in mucosal tissue is regulated by the balance between these cytokines. The short allele IL1RN*2, is associated with increased levels of IL1B, which could probably have a significant effect on increased inflammatory damage (Santtila et al., 1998).
It has also been described that IL1B inhibits gastric secretion (Sugimoto et al., 2009), and it is 100 times more potent than proton pump inhibitor (Wolfe and Nompleggi, 1992), which favors the corpus colonization, causing atrophic gastritis that may evolve to gastric carcinoma. El-Omar and cols., demonstrated an increased risk of hypochlorhydria when IL1RN*2 allele is present in homozygous form (El-Omar et al., 2000).

Cervical cancer

Cervical cancer is associated with the infection by human papillomavirus (HPV), however, although millions of women are infected with high-risk HPV subtypes, only a subset of them develop cervical cancer, reveling an important role of host immunity in cervical carcinogenesis. Various studies have observed a significant contribution of IL1RN*2 allele to increase risk of cervical cancer (Sehouli et al., 2002; Mustea et al., 2003; Tamandani et al., 2008; Sousa et al., 2012). Moreover, Sousa and cols, found that IL1RN*2 correlated not only with cervical cancer but with cervical lesions and earlier onset of cases with cervical lesion and cancer in patients homozygous IL1RN*2 (Sousa et al., 2012). Tamandani and cols, showed a protective association of heterozygous IL1RN*1*2 and homozygous IL1RN*2 and HPV 16 and 18 subtypes but a risk association with adenocarcinoma (Tamandani et al., 2008).

Breast cancer

In Caucasian women it has been described that IL1RN*2 is associated with shortened disease free survival and overall survival (Grimm et al., 2009). In this study, Grimm and cols reported that only 80% of women positive to IL1RN*2 survived after 12 months, and 30% had died after 48 months; the disease-free survival was only of 40% in women with IL1RN*2 compared with 80% in women with the wild allele (Grimm et al., 2009). In respect to the long alleles of IL1RN gene, allele *2 has been reported to be modify the binding on the IL1 receptor, leading to less efficient inhibition of IL1a and IL1b (Tarlow et al., 1993), this might result in a proinflammatory status and enhanced tumor aggressiveness, which is likely to result in a shortened survival of women with breast cancer (Grimm et al., 2009).

Breast cancer oncogenesis has been associated with polymorphisms in different cytokines (Gomez-Flores-Ramos et al., 2013; Dinarello, 2006) and it has been widely discuss the participation of chronic inflammation in breast carcinogenesis (Honma et al., 2002). Different research groups have studied the association of IL1RN and breast cancer risk. Lee and cols, found a decreased breast cancer risk with the short allele (*2) and a higher risk of cancer in women with the long allele and higher body mass index (Lee et al., 2006). Zhang and cols, performed a meta-analysis study and found a similar trend with allele IL1RN*2 (Zhang et al., 2011), however, with this apparent diminish in risk for breast cancer, other studies have found an elevated risk of earlier recurrence of breast cancer in women with IL1RN*2 allele (Grimm et al., 2009).

Bladder cancer

Significant association with higher risk of bladder cancer has been described to Il1RN*2 allele (Bid et al., 2006; Ahirwar et al., 2009). This allele has been proposed as a potential marker for genetic susceptibility to bladder cancer (Ahirwar et al., 2009). Studies have showed that IL1RN*2 increases the production of IL1B significantly (Santtila et al., 1998; Nazarenko et al., 2008) and it can induce angiogenesis via upregulation of COX-2 or inducible nitric oxide and vascular endothelial growth factor which may contribute to tumor growth (Rahman et al., 2001).

Colorectal cancer

IL1B and IL1RN have been shown to play an important role in angiogenesis of early onset tumors, Viet and cols, found that allele *1 was more frequent in patients with localized disease compared with disseminated disease, being allele *2 associated with dissemination of the disease (Viet et al., 2005). The study of Lurje and cols, showed that patients with IL1RN VNTR had a significant six-fold increment in relative risk of developing tumor recurrence compared to those patients with the wild allele. The IL1RN homozygous *2/*2 genotype had a median time-to-recurrence of 5.7 years, compared with 10.7 years for those with *1/*1 genotype (Lurje et al., 2009).
Serum levels of IL1Ra have been studies as prognostic factors as well, in colorectal cancer patients, low preoperative IL1Ra was associated with postoperative infection (Miki et al., 2005).

Colorectal cancer has been widely associated in epidemiological and experimental studies with chronic inflammation. Viet and cols, found that the allele IL1RN*3 of VNTR variant was significantly increased in patients compared with controls, and the allelic distribution of this VNTR differed between colon and rectum, being allele *3 more abundant in colon (Viet et al., 2005). Other polymorphic sites have been associated with colorectal oncogenesis. Burada and cols, linked the polymorphism IL1RN +2018C>T with colorectal cancer, allele C was found to be enriched in patients with cancer compared to controls. This study described that this association was limited to early stage I and II (Burada et al., 2013).
In attempt to find markers for colorectal cancer disease, serum cytokines levels have been studied; Iwagaki and cols, found that patients with colorectal cancer present reduced level of IL1Ra relative to normal controls, indicating that cancer patients have an immunologic disorder (Iwagaki et al., 1997).

Lung cancer

Tobacco smoking is the main risk factor for lung cancer, however, only 10-15% of smokers develop lung cancer, suggesting that genetic factors are important in individual susceptibility for this disease (Ridge et al., 2013). Lind and cols, found that individuals homozygous for IL1RN*1 in combination with the allele IL1B-31T had an increased risk of non-small cell lung cancer and a two-fold higher level of bulky/hydrophobic DNA adducts in the long in patients with IL1RN*1 (Lind et al., 2005). These data were confirmed in Chinese patients, with a decreased risk of 32% in patients with IL1RN*2 allele (Hu et al., 2006). On the other hand, Lim and cols, found a 5-fold-time increased risk in lung cancer in never-smokers patients with the IL1RN*2 (Lim et al., 2011), but these results are not consistent, since Hu and cols, found a reduced risk in non-smokers with squamous cell carcinoma (Hu et al., 2006).

Brain cancer

Inflammatory status of brain tumors has been studied, and it has been shown that IL1 cluster is important in development and progression of neoplasia. Ilyin and cols, investigated the levels of IL1 and IL1Ra in pediatric astrocytomas, ependymomas and primitive neuroectodermal tumors. The results demonstrated a significant different profile among tumors. Pilocytic, nonpilocytic and anaplastic astrocytomas had a significant increase of mRNA of IL1 beta and its receptor, but low levels of IL1Ra mRNA, suggesting an imbalance between stimulatory and inhibitory cytokines in brain tumors growth and development via autocrine/paracrine mechanisms (Ilyin et al., 1998).
Oelmann and cols, performed a study in cell lines of glioblastoma showed that IL1Ra modulates glioblastoma growth. Experimental addition of neutralizing antibody against IL1Ra down-regulated growth of IL1 and IL1Ra producing glioblastoma, the authors suggest that an autocrine production of IL1Ra can counteract IL1 function and represent a basic escape mechanism malignant growth in some glioblastomas (Oelmann et al., 1997).

Septic shock in pediatric population with acute lymphoblastic leukemia

The presence of IL1RN*2 allele was associated with significant susceptibility to septic shock in pediatric patients with acute lymphoblastic leukemia by (Zapata-Tarres et al., 2013). The patients studied by Zapata-Tarres and cols, were susceptible to septic shock. The association between sepsis and IL1RN*2 has been reported previously, Fang and cols, reported an increased relative risk of sepsis in patients homozygous IL1RN*2 as well heterozygous patients (Fang et al., 1999). Arnalich and cols reported a significant increase in the risk of death after severe sepsis in patients with IL1RN*2 and that the allele is associated with decreased production of IL1Ra in culture but higher concentrations of the protein in serum (Arnalich et al., 2002).