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IL1RN (interleukin 1 receptor antagonist)

Written2014-03Liliana Gómez-Flores-Ramos, Jorge Torres-Flores, Martha Patricia Gallegos-Arreola
Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Division de Medicina Molecular, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico (LGFR); Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Division de Inmunologia, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico (JTF); Division de Medicina Molecular, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico (MPGA)

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)IL1RA
ICIL-1RA
IL1F3
IRAP
IL-1RN
MGC10430
Other aliasDIRA
IL-1ra
IL-1ra3
MVCD4
HGNC (Hugo) IL1RN
LocusID (NCBI) 3557
Atlas_Id 40953
Location 2q13  [Link to chromosome band 2q13]
Location_base_pair Starts at 113117893 and ends at 113134016 bp from pter ( according to hg19-Feb_2009)  [Mapping IL1RN.png]
Local_order IL1RN is located between PSD4 gene (pleckstrin and Sec7 domain containing 4) and IL36RN (interleukin 36 receptor antagonist) and IL1F10 (interleukin 1 family, member 10 (theta)) genes (NCBI).
 
  IL1RN locus is 2q13. The gene length is 22901 bp (starts at 113868692 - ends at 113891592, according NCBI 08-Jul-2013). In this region is located along with IL36RN, IL1F10 and PSD4 and PAX8.
Fusion genes
(updated 2016)
ATP6V1E1 (22q11.21) / IL1RN (2q13)IL1RN (2q13) / CDK11B (1p36.33)IL1RN (2q13) / IL1RN (2q13)
IL1RN (2q13) / NUCKS1 (1q32.1)IL1RN (2q13) / PARP4 (13q12.12)PUM2 (2p24.1) / IL1RN (2q13)

DNA/RNA

Note IL1RN (interleukin 1 receptor antagonist) was identified in 1990 by Carter and cols (Carter et al., 1990). It codes a protein that binds to interleukin 1 receptor (IL1R1) and inhibits the binding of interleukin 1 alpha and beta (IL1A and IL1B), blocking the biological activity of these two cytokines, this is the first interleukin 1 family member described that has antagonist function (Arend, 1991; Arend and Gabay, 2000). This gene is overexpressed in different infectious diseases and immune conditions. The IL1RN gene has a length of 22901 base-pairs, and is constituted by 6 exons; there are four isoforms described to date that are produced by alternative splicing: one isoform is secreted and the other three are cytoplasmic (Gabay et al., 1997; Arend and Guthridge, 2000).
 
  Linear diagram of IL1RN gene with their 6 exons (pink boxes).
Description The IL1RN gene has a length of 22901 base-pairs, encodes a member of the interleukin 1 cytokine family. The gene is located on 2q13.
Transcription 6 exons; mRNA linear (NM_173842.2) with 1794 bp. IL1RN mRNA does not contain the AUUUA sequence that has been implicated in shortening the half-life of several cytokine mRNAs (Carter et al., 1990).
Pseudogene No pseudogenes have been identified.

Protein

Note The IL1RN precursor protein consists of 177 amino acids and has a molecular weight of 20055 Daltons. The IL1RN cDNA encodes a 152 amino acid protein preceded by a 25 amino acid secretory leader sequence indicating that this protein takes a more straightforward pathway out of the cell than IL1. IL1RN is found extracellularly in its mature form without requiring extracellular cleavage to its mature form. The mature protein consists in ~159 amino acids (Arend, 1991; Haskill et al., 1991).
The IL1RN gene produces two forms of IL1RN: intracellular (icIL1RN) and secreted (sIL1RN) which are controlled by different promoter regions (Redlitz et al., 2004).
 
  Table of four IL1RN isoforms, showing the amino acid sequences and other protein characteristics.
Description The protein consists of 177 amino acids, and a molecular weight of 20KDa. The amino acid sequence homology is 26-30% to IL1β and 19% to IL1α. The mature protein is a single nonglycosylated polypeptide of 150 amino acids approximately, further, this protein contains a 25 amino acids leader sequence (Eisenberg et al., 1990).
Expression Practically, IL1RN is expressed in whole organism, in both adult and embryonic stages. IL1RN is expressed physiologically in different tissues like lymph node, brain, heart, colon, adipocyte, kidney, liver, lung, thyroid, adrenal gland, skin, placenta, ovary, prostate and testis (GeneCards). Furthermore, IL1RN is present in numerous cancers such as gastric cancer (Iizuka et al., 1999), cervical cancer (Fujiwaki et al., 2003), lymphoblastic (Hulkkonen et al., 2000) and myelogenous (Estrov et al., 1992) leukemias, breast cancer (Miller et al., 2000), endometrial cancer (Van Le et al., 1991), bladder cancer (Ahirwar et al., 2009), colorectal cancer (Viet et al., 2005), lung cancer (Lind et al., 2005) and brain tumors (Oelmann et al., 1997; Ilyin et al., 1998).
Localisation There are four isoforms of IL1RN. The IL1RN isoform 1 is secreted, and the other three, IL1RN2, IL1RN3 and IL1RN4 have localization into cytoplasm (Arend and Guthridge, 2000).
Function The protein binds to interleukin 1 receptor (IL1R1) and inhibits the binding of interleukin 1 alpha and beta (IL1A and IL1B) (Arend, 1991; Arend and Gabay, 2000), modulating the immune response (Dinarello, 2011). IL1RN competes with IL1 for binding two IL1 cell surface receptors type I and type II (IL1RtI and IL1RtII), however, when it occupies the receptor it does not trigger the cellular responses typical of IL1 which includes the production of secondary substances that mediate inflammatory responses and tissue remodeling (Dinarello, 2011).
 
  When IL1 binds to IL1-receptor induces proinflammatory reaction and gene expression. Blocking of the receptor by IL1RN prevents this response.
Homology Homologs of IL1RN protein are highly conserved in different species (NCBI).
Rattus norvegicus: Il1rn (178 amino acids).
Mus musculus: Il1rn (159 aa).
Equus caballus: IL1RN (177 aa).
Bos taurus: IL1RN (174 aa).
Canis lupus familiaris: IL1RN (176 aa).
Tursiops truncatus: IL1RN (177 aa).
Gallus gallus: IL1RN (163 aa).
Macaca fascicularis: IL1RN (177 aa).

Mutations

Note Allelic variants
Germinal The most common variation in the IL1RN gene is the penta allelic variable number of tandem repeat of 86 base pair located in intron 2 which results in a short allele with two repeats (IL1RN*2), and long alleles (IL1RN*L): allele 1 (four repeats), allele 3 (five repeats), allele 4 (three repeats) and allele 5 (six repeats). The most frequent allelic form is allele 1 followed by allele 2, the rest of the alleles are very rare. It has been reported that the allele 2 causes a 10-fold increased seric IL1RN (Danis et al., 1995). Furthermore, Redlitz and cols, found that allele 1 has a 4-fold increase of the production of icIL1RN compared to allele 1 (Redlitz et al., 2004).
Two other germline mutations: Gln57Ter (rs121913162) and Glu80Ter (rs121913161) have been associated with the deficiency of IL1RN leaning to an autoinflammatory (Aksentijevich et al., 2009).
Somatic The somatic mutation rs148026279 producing the protein change Phe148Val has been associated with malignant melanoma (Wei et al., 2011).

Implicated in

Note
  
Entity Various cancers
Note 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).
  
  
Entity Gastric cancer
Note 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).
Oncogenesis 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).
  
  
Entity Cervical cancer
Oncogenesis 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).
  
  
Entity Breast cancer
Prognosis 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).
Oncogenesis 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).
  
  
Entity Bladder cancer
Oncogenesis 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).
  
  
Entity Colorectal cancer
Prognosis 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).
Oncogenesis 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).
  
  
Entity Lung cancer
Oncogenesis 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).
  
  
Entity Brain cancer
Oncogenesis 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).
  
  
Entity Septic shock in pediatric population with acute lymphoblastic leukemia
Prognosis 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).
  

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Mattar R, Marques SB, Dos Santos AF, do Socorro Monteiro M, Iriya K, Carrilho FJ.
Clin Exp Gastroenterol. 2013 Apr 18;6:35-41. doi: 10.2147/CEG.S42260. Print 2013.
PMID 23637547
 
Deficiency in systemic interleukin-1 receptor antagonist production as an operative risk factor in malnourished elderly patients with colorectal carcinoma.
Miki C, Inoue Y, Toiyama Y, Ojima E, Kobayashi M, Hatada T, Araki T, Kusunoki M.
Crit Care Med. 2005 Jan;33(1):177-80.
PMID 15644666
 
Interleukin-1 family expression in human breast cancer: interleukin-1 receptor antagonist.
Miller LJ, Kurtzman SH, Anderson K, Wang Y, Stankus M, Renna M, Lindquist R, Barrows G, Kreutzer DL.
Cancer Invest. 2000;18(4):293-302.
PMID 10808364
 
Gastric cancer and the high combination prevalence of host cytokine genotypes and Helicobacter pylori in Honduras.
Morgan DR, Dominguez RL, Keku TO, Heidt PE, Martin CF, Galanko JA, Omofoye OA, Sandler RS.
Clin Gastroenterol Hepatol. 2006 Sep;4(9):1103-11. Epub 2006 Jul 3.
PMID 16820326
 
Interleukin 1 receptor antagonist (IL-1RA) polymorphism in women with cervical cancer.
Mustea A, Sehouli J, Konsgen D, Stengel D, Sofroni D, Lichtenegger W.
Anticancer Res. 2003 Mar-Apr;23(2A):1099-102.
PMID 12820354
 
Tumorigenicity of IL-1alpha- and IL-1beta-deficient fibrosarcoma cells.
Nazarenko I, Marhaba R, Reich E, Voronov E, Vitacolonna M, Hildebrand D, Elter E, Rajasagi M, Apte RN, Zoller M.
Neoplasia. 2008 Jun;10(6):549-62.
PMID 18516292
 
Autocrine interleukin-1 receptor antagonist can support malignant growth of glioblastoma by blocking growth-inhibiting autocrine loop of interleukin-1.
Oelmann E, Kraemer A, Serve H, Reufi B, Oberberg D, Patt S, Herbst H, Stein H, Thiel E, Berdel WE.
Int J Cancer. 1997 Jun 11;71(6):1066-76.
PMID 9185713
 
IL-1ra anti-inflammatory cytokine polymorphism is associated with risk of gastric cancer and chronic gastritis in a Brazilian population, but the TNF-b pro-inflammatory cytokine is not.
Oliveira JG, Duarte MC, Silva AE.
Mol Biol Rep. 2012 Jul;39(7):7617-25. doi: 10.1007/s11033-012-1596-x. Epub 2012 Feb 12.
PMID 22327782
 
Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population.
Palli D, Saieva C, Luzzi I, Masala G, Topa S, Sera F, Gemma S, Zanna I, D'Errico M, Zini E, Guidotti S, Valeri A, Fabbrucci P, Moretti R, Testai E, del Giudice G, Ottini L, Matullo G, Dogliotti E, Gomez-Miguel MJ.
Am J Gastroenterol. 2005 Sep;100(9):1941-8.
PMID 16128937
 
IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis.
Queiroz DM, Guerra JB, Rocha GA, Rocha AM, Santos A, De Oliveira AG, Cabral MM, Nogueira AM, De Oliveira CA.
Gastroenterology. 2004 Jul;127(1):73-9.
PMID 15236174
 
Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases.
Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H, Ono T, Yamanoi A, Kohno H, Nagasue N.
Clin Cancer Res. 2001 May;7(5):1325-32.
PMID 11350902
 
Differential contribution of IL-1Ra isoforms to allele-specific IL-1Ra mRNA accumulation.
Redlitz KH, Yamshchikov VF, Cominelli F.
J Interferon Cytokine Res. 2004 Apr;24(4):253-60.
PMID 15144571
 
Epidemiology of Lung Cancer.
Ridge CA, McErlean AM, Ginsberg MS.
Semin Intervent Radiol. 2013 Jun;30(2):93-98. (REVIEW)
PMID 24436524
 
The IL-1 and IL-1 receptor antagonist (IL-1Ra) response of human neutrophils to EBV stimulation. Preponderance of IL-Ra detection.
Roberge CJ, Poubelle PE, Beaulieu AD, Heitz D, Gosselin J.
J Immunol. 1996 Jun 15;156(12):4884-91.
PMID 8648138
 
IL1RN polymorphic gene and cagA-positive status independently increase the risk of noncardia gastric carcinoma.
Rocha GA, Guerra JB, Rocha AM, Saraiva IE, da Silva DA, de Oliveira CA, Queiroz DM.
Int J Cancer. 2005 Jul 10;115(5):678-83.
PMID 15704154
 
Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro.
Santtila S, Savinainen K, Hurme M.
Scand J Immunol. 1998 Mar;47(3):195-8.
PMID 9519856
 
Polymorphism of IL-1 receptor antagonist gene: role in cancer.
Sehouli J, Mustea A, Konsgen D, Katsares I, Lichtenegger W.
Anticancer Res. 2002 Nov-Dec;22(6A):3421-4.
PMID 12530098
 
Relation of atrophic gastritis with Helicobacter pylori-CagA(+) and interleukin-1 gene polymorphisms.
Sierra R, Une C, Ramirez V, Alpizar-Alpizar W, Gonzalez MI, Ramirez JA, De Mascarel A, Cuenca P, Perez-Perez G, Megraud F.
World J Gastroenterol. 2008 Nov 14;14(42):6481-7.
PMID 19030199
 
IL-1RN VNTR polymorphism and genetic susceptibility to cervical cancer in Portugal.
Sousa H, Santos AM, Catarino R, Pinto D, Moutinho J, Canedo P, Machado JC, Medeiros R.
Mol Biol Rep. 2012 Dec;39(12):10837-42. doi: 10.1007/s11033-012-1979-z. Epub 2012 Oct 10.
PMID 23053980
 
Influence of inflammatory cytokine polymorphisms on eradication rates of Helicobacter pylori.
Sugimoto M, Furuta T, Yamaoka Y.
J Gastroenterol Hepatol. 2009 Nov;24(11):1725-32. doi: 10.1111/j.1440-1746.2009.06047.x. (REVIEW)
PMID 20136959
 
Impact of polymorphism in IL-1RA gene on the risk of cervical cancer.
Tamandani DM, Sobti RC, Shekari M, Kaur S, Huria A.
Arch Gynecol Obstet. 2008 Jun;277(6):527-33.
PMID 18008080
 
Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat.
Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A, Duff GW.
Hum Genet. 1993 May;91(4):403-4.
PMID 8500797
 
Expression of interleukin-1 and interleukin-1 receptor antagonists in endometrial cancer.
Van Le L, Haskill S, Jaffe GJ, Fowler WC Jr.
Gynecol Oncol. 1991 Aug;42(2):161-4.
PMID 1832651
 
Interleukin-1 receptor antagonist gene polymorphism in human colorectal cancer.
Viet HT, Wagsater D, Hugander A, Dimberg J.
Oncol Rep. 2005 Oct;14(4):915-8.
PMID 16142351
 
Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.
Wang Y, Kato N, Hoshida Y, Yoshida H, Taniguchi H, Goto T, Moriyama M, Otsuka M, Shiina S, Shiratori Y, Ito Y, Omata M.
Hepatology. 2003 Jan;37(1):65-71.
PMID 12500190
 
Exome sequencing identifies GRIN2A as frequently mutated in melanoma.
Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S; NISC Comparative Sequencing Program, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y.
Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15.
PMID 21499247
 
Cytokine inhibition of gastric acid secretion--a little goes a long way.
Wolfe MM, Nompleggi DJ.
Gastroenterology. 1992 Jun;102(6):2177-8.
PMID 1587446
 
Interleukin-1 receptor antagonist gene polymorphism increases susceptibility to septic shock in children with acute lymphoblastic leukemia.
Zapata-Tarres M, Arredondo-Garcia JL, Rivera-Luna R, Klunder-Klunder M, Mancilla-Ramirez J, Sanchez-Urbina R, Vazquez-Cruz MY, Juarez-Villegas LE, Palomo-Colli MA.
Pediatr Infect Dis J. 2013 Feb;32(2):136-9. doi: 10.1097/INF.0b013e31827566dd.
PMID 23014359
 
Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.
Zhang B, Beeghly-Fadiel A, Long J, Zheng W.
Lancet Oncol. 2011 May;12(5):477-88. doi: 10.1016/S1470-2045(11)70076-6. Epub 2011 Apr 20. (REVIEW)
PMID 21514219
 

Citation

This paper should be referenced as such :
L Gè_mez-Flores-Ramos, J Torres-Flores, MP Gallegos-Arreola
IL1RN (interleukin 1 receptor antagonist)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(10):746-753.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IL1RNID40953ch2q13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Vulva and Vagina tumors: an overview


External links

Nomenclature
HGNC (Hugo)IL1RN   6000
LRG (Locus Reference Genomic)LRG_188
Cards
AtlasIL1RNID40953ch2q13
Entrez_Gene (NCBI)IL1RN  3557  interleukin 1 receptor antagonist
AliasesDIRA; ICIL-1RA; IL-1RN; IL-1ra; 
IL-1ra3; IL1F3; IL1RA; IRAP; MVCD4
GeneCards (Weizmann)IL1RN
Ensembl hg19 (Hinxton)ENSG00000136689 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000136689 [Gene_View]  chr2:113117893-113134016 [Contig_View]  IL1RN [Vega]
ICGC DataPortalENSG00000136689
TCGA cBioPortalIL1RN
AceView (NCBI)IL1RN
Genatlas (Paris)IL1RN
WikiGenes3557
SOURCE (Princeton)IL1RN
Genetics Home Reference (NIH)IL1RN
Genomic and cartography
GoldenPath hg38 (UCSC)IL1RN  -     chr2:113117893-113134016 +  2q14.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IL1RN  -     2q14.1   [Description]    (hg19-Feb_2009)
EnsemblIL1RN - 2q14.1 [CytoView hg19]  IL1RN - 2q14.1 [CytoView hg38]
Mapping of homologs : NCBIIL1RN [Mapview hg19]  IL1RN [Mapview hg38]
OMIM137215   147679   612628   612852   
Gene and transcription
Genbank (Entrez)AF043143 AJ005835 AK290898 AK290926 BC009745
RefSeq transcript (Entrez)NM_000577 NM_001318914 NM_173841 NM_173842 NM_173843
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)IL1RN
Cluster EST : UnigeneHs.81134 [ NCBI ]
CGAP (NCI)Hs.81134
Alternative Splicing GalleryENSG00000136689
Gene ExpressionIL1RN [ NCBI-GEO ]   IL1RN [ EBI - ARRAY_EXPRESS ]   IL1RN [ SEEK ]   IL1RN [ MEM ]
Gene Expression Viewer (FireBrowse)IL1RN [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3557
GTEX Portal (Tissue expression)IL1RN
Protein : pattern, domain, 3D structure
UniProt/SwissProtP18510   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP18510  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP18510
Splice isoforms : SwissVarP18510
PhosPhoSitePlusP18510
Domaine pattern : Prosite (Expaxy)INTERLEUKIN_1 (PS00253)   
Domains : Interpro (EBI)IL-1_CS    IL-1_fam    IL-1RA/IL-36    IL1/FGF   
Domain families : Pfam (Sanger)IL1 (PF00340)   
Domain families : Pfam (NCBI)pfam00340   
Conserved Domain (NCBI)IL1RN
DMDM Disease mutations3557
Blocks (Seattle)IL1RN
PDB (SRS)1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
PDB (PDBSum)1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
PDB (IMB)1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
PDB (RSDB)1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
Structural Biology KnowledgeBase1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
SCOP (Structural Classification of Proteins)1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
CATH (Classification of proteins structures)1ILR    1ILT    1IRA    1IRP    1ITN    2IRT   
SuperfamilyP18510
Human Protein AtlasENSG00000136689
Peptide AtlasP18510
HPRD00978
IPIIPI00000045   IPI00175024   IPI00218573   IPI00174541   
Protein Interaction databases
DIP (DOE-UCLA)P18510
IntAct (EBI)P18510
FunCoupENSG00000136689
BioGRIDIL1RN
STRING (EMBL)IL1RN
ZODIACIL1RN
Ontologies - Pathways
QuickGOP18510
Ontology : AmiGOcytokine activity  interleukin-1, Type I receptor binding  interleukin-1, Type II receptor binding  interleukin-1 receptor antagonist activity  interleukin-1 receptor antagonist activity  protein binding  extracellular space  intracellular  cytoplasm  plasma membrane  lipid metabolic process  inflammatory response  immune response  insulin secretion  negative regulation of heterotypic cell-cell adhesion  interleukin-1 Type I receptor antagonist activity  interleukin-1 Type II receptor antagonist activity  response to glucocorticoid  extracellular exosome  negative regulation of interleukin-1-mediated signaling pathway  
Ontology : EGO-EBIcytokine activity  interleukin-1, Type I receptor binding  interleukin-1, Type II receptor binding  interleukin-1 receptor antagonist activity  interleukin-1 receptor antagonist activity  protein binding  extracellular space  intracellular  cytoplasm  plasma membrane  lipid metabolic process  inflammatory response  immune response  insulin secretion  negative regulation of heterotypic cell-cell adhesion  interleukin-1 Type I receptor antagonist activity  interleukin-1 Type II receptor antagonist activity  response to glucocorticoid  extracellular exosome  negative regulation of interleukin-1-mediated signaling pathway  
Pathways : BIOCARTASignal transduction through IL1R [Genes]   
REACTOMEP18510 [protein]
REACTOME PathwaysR-HSA-6783783 [pathway]   
NDEx NetworkIL1RN
Atlas of Cancer Signalling NetworkIL1RN
Wikipedia pathwaysIL1RN
Orthology - Evolution
OrthoDB3557
GeneTree (enSembl)ENSG00000136689
Phylogenetic Trees/Animal Genes : TreeFamIL1RN
HOVERGENP18510
HOGENOMP18510
Homologs : HomoloGeneIL1RN
Homology/Alignments : Family Browser (UCSC)IL1RN
Gene fusions - Rearrangements
Fusion : MitelmanPUM2/IL1RN [2p24.1/2q13]  [t(2;2)(p24;q13)]  
Fusion: TCGAPUM2 2p24.1 IL1RN 2q13 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIL1RN [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IL1RN
dbVarIL1RN
ClinVarIL1RN
1000_GenomesIL1RN 
Exome Variant ServerIL1RN
ExAC (Exome Aggregation Consortium)IL1RN (select the gene name)
Genetic variants : HAPMAP3557
Genomic Variants (DGV)IL1RN [DGVbeta]
DECIPHERIL1RN [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIL1RN 
Mutations
ICGC Data PortalIL1RN 
TCGA Data PortalIL1RN 
Broad Tumor PortalIL1RN
OASIS PortalIL1RN [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIL1RN  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIL1RN
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch IL1RN
DgiDB (Drug Gene Interaction Database)IL1RN
DoCM (Curated mutations)IL1RN (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IL1RN (select a term)
intoGenIL1RN
NCG5 (London)IL1RN
Cancer3DIL1RN(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM137215    147679    612628    612852   
Orphanet18683   
MedgenIL1RN
Genetic Testing Registry IL1RN
NextProtP18510 [Medical]
TSGene3557
GENETestsIL1RN
Target ValidationIL1RN
Huge Navigator IL1RN [HugePedia]
snp3D : Map Gene to Disease3557
BioCentury BCIQIL1RN
ClinGenIL1RN
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3557
Chemical/Pharm GKB GenePA29816
Clinical trialIL1RN
Miscellaneous
canSAR (ICR)IL1RN (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIL1RN
EVEXIL1RN
GoPubMedIL1RN
iHOPIL1RN
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:05:18 CEST 2017

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