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	�:	Journal of Molecular Biomarkers & Diagnosis
Short name: J Mol Biomark Diagn
Volume 11: 6, 2020	
A Significant Association of IL1R2 Draiii T/G Polymorphism with the Risk of Gall Bladder Cancer in Ethnic Kashmiri Population
Malik Gawharul Haq#1, Sabzar A Malik#1, Imtiyaz A Bhat1, Sadaf Ali2, Arshad A Pandith3, Omer J Shah2, Zafar A Shah1*
�Department of Immunology and Molecular Medicine, SKIMS Srinagar, India
2Advanced Center for Human genetics, SKIMS, Srinagar, India
3Department of Surgical Gastroenterology, SKIMS, Srinagar, India
#Both the authors contributed equally.
Abstract
Background: Chronic inflammation is considered as an emerging area of research interest because of its cognize association with different organ cancers. Recent advances in cancer research have substantiated that targeting cytokines have a strong therapeutic potential in reducing the mortality of inflammation-related cancers. Gallbladder cancer (GBC) has been consistently associated with inflammation mostly due to presence of gallstones which prelude inflammatory response. The Interleukin-1 (IL1) gene cluster serves an important function of immunomodulation, thereby regulating interplay between inflammation and cancer. Studies on the association of IL1 polymorphisms with GS and GBC have shown drastic variations in different populations. Since no such study has been carried out in ethnic Kashmiri population which is known for high incidence of GS disease, we aimed to evaluate the possible role of pro-inflammatory IL1 family in the pathogenesis of GBC and GS disease. 
Methods: A total of 370 individuals (120 GBC, 120 GS and 130 healthy controls) were prospectively recruited. The study analyzed various polymorphisms of IL1 gene family to predict their association with GBC and gallstone disease. PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) was used for genotyping and SPSS 23.0 software was used to calculate odds ratios (ORs) and confidence intervals (CIs). Tissue-specific expression of IL-1� was done by Quantitative Real-time PCR (qRT-PCR) and the data was analyzed by Graph Pad Prism version 5. 
Results: IL1R2 T/G DraIII 'GG' genotype (OR: 2.65, 95% CI: 1.27-5.53, P = 0.011) and 'G' allele (OR: 1.57, 95% CI: 1.10-2.24, P = 0.014) indicated a positive association with GBC. Two polymorphisms in the IL1 gene family (IL-1� +4845G/T and IL1R1Pst1C/T) were observed to be insignificant towards GBC in our study cohort. IL-1� mRNA expression did not differ between tumor and adjacent normal GB tissues. Above all none of the studied polymorphisms was significant towards gallstone disease.
Conclusion:  We conclude that IL1R2 DraIII T/G SNP bears a significant association with GBC and could be an important etiological factor for GBC in our population.
Keywords: Gall Bladder Cancer � Inflammation � Interleukins � Polymorphisms � mRNA expression
Abbreviations: GBC: Gallblader Cancer; GS: Gall Stone disease; IL: Interleukin; PCR: Polymerase Chain Reaction; OR: Odds Ratio; CI: Confidence Interval.
*Address for Correspondence: Shah ZA, Department of Immunology and Molecular Medicine, SKIMS Srinagar, India, E-mail: zaffar.amin@skims.ac.in
Copyright: � 2020 Haq MG, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 08 October, 2020; Accepted: 23 October, 2020; Published: 30 October, 2020
Introduction
Gallbladder cancer (GBC) is a multi-factorial disease with diverse risk factors including gallstones, obesity, reproductive factors, chronic infection, and environmental exposure to specific chemicals [1-4]. It is the fifth most common malignant neoplasm of the digestive tract and despite recent advances in the diagnosis and management of gastrointestinal cancers, this cancer presents with a dismal prognosis [5]. The frequency of this cancer increases with age and reaches peak value after fifth decade of life [6]. Worldwide incidence shows striking gender bias and affects females 2�3 times more frequently as compared to males [7].  
GBC has been consistently associated with inflammation due to presence of gallstones, blockade of pancreato-biliary duct and chronic infection and intriguingly 1~3% patients of gallstone disease develop gallbladder cancer at any stage of life [8-12]. Accountable of evidences point that genetic susceptibility may contribute to gallbladder carcinogenesis [13,14], however the precise mechanism leading to GBC transformation is yet to be elucidated [15]. It is increasingly recognized that inflammatory pathway genes show association with GBC [16,17]. Whereas the unparalleled role of inflammation in different organ cancers like lung and colorectal cancer is well established, there is limited replicated data that can strongly establish its putative role in GBC [18-21].
Inflammation is a cascade of reactions involving a vast array of genes. Of utmost importance with particular inception towards GBC are the genes of IL1 family and prostaglandin synthases (cyclooxygenases). The IL-1 gene located on chromosome 2q14encodes proteins that are involved in promoting fever, activation of prostaglandin endoperoxide synthase2 (PTGS2) [13] and differentiation of autoimmune disorders notably monogenic conditions referred as cryopyrin associated periodic syndromes (CAPS) [14]. In addition IL1 is known to activate vascular endothelial growth factor (VEGF), can trigger the process of angiogenesis [22] and can directly affect gallbladder epithelial cell absorptive function [23].
It has been observed that at least 40% of malignancies worldwide are infectious and inflammation based which accounts for a total of more than 3 million cases per year [24,25]. With respect to GBC, data shows that approximately 50% patients have a history suggestive of chronic inflammation [26-28]. In a population-based study conducted in Shanghai, China, usage of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with a significant 63% reduction in the risk of GBC and it has been already suggested that it can be in-part due to blockade of inflammatory pathway genes or by limiting the activity of prostaglandin synthases [29].
While most of the proteins are controlled by regulated expression, some of their functions are controlled by key polymorphic variants (SNPs) which can potentially alter the splicing process, modify the binding of transcription factors, affect the stability of mRNA or remould the structure of the enzyme. Single nucleotide polymorphisms in Interleukin-1 have been associated regularly with inflammation based cancers including GB cancer, lung cancer and gastric cancer [30-32]. Owing to their role in induction [33] and over expression of associated molecules in neoplastic tissues, including the biliary-tree [34-37], the present study was designed to investigate the role of key polymorphic variants of IL-1 gene family and IL-1� expression in affecting susceptibility to GB cancer and gallstone disease in Kashmiri population. To date, no studies have examined the role of respective IL1 polymorphisms with the risk of GBC or gallstones in this region.
Subject selection and recruitment
A total of 120 GBC patients, 120 Gall stone Patients and 130 age and sex matched controls were prospectively included. The GBC and gall stone patients were recruited from the Department of Surgical Gastroenterology, Department of General Surgery and Department of Surgical Oncology, Sheri-Kashmir Institute of Medical Sciences (SKIMS) after proper evaluation and diagnosis. 
Before sample collection, the participants were informed about the nature of the study and its possible outcome and a written consent was taken. The study was approved by the Institutional Ethics Committee, Skims Vide approval no138/2013. 
Materials and Methods
Genotyping
Genomic DNA was isolated from blood samples by phenol chloroform. Prior to genotyping DNA quality and content was checked by Agarose gel electrophoresis and spectrophotometry respectively (Nanodrop Spectrophotometer, Eppendorf AG, Hamburg, Germany). 
Polymerase chain reaction (PCR) was performed using an iCycler Thermal Cycler (Agilent technologies, Malaysia). Respective genotypes of IL-1� +4845G/T, IL1R1 Pst1 and IL1R2DraIII polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Specific primers were designed and selected using Primer3, version 0.4.0 software. The list of primers and restriction enzymes utilized are presented in Table-1.
The PCR reaction mixture consisted of Taq DNA polymerase 1.0 U (Ferments), forward and reverse primers (0.5 �mol/l), MgCl2 (50 mmol/l), dNTPs (0.2 mmol/l), and DNA template (250ng-500ng) and was subjected to an initial denaturing step of 5 min at 95 �C, then 35 cycles of denaturing for 35s at 95 �C, annealing for 35sfollowed by extension for 35 s at 72 �C, and a final extension step of 10 min at 72 �C. Digestion of the amplified products was carried out by restriction endonucleases (Table-1) by incubation at 37 �C for 16 h. The digested products were resolved on 3% agaroses gel. Furthermore to clarify results, genotyping was randomly repeated on 5% of samples.
mRNA expression analysis
Total RNA was extracted from gallbladder tumor and adjacent normal tissue specimens by using TRIZOL (Sigma Aldrich, USA). Integrity of the mRNA was checked on 1% agarose gel and quantified at 260/280 ratio. Prior to cDNA synthesis, DNAse treatment was given to extracted RNA to remove any traces of genomic DNA. cDNA was synthesized according to manufactures protocol (Fermentas, USA). qRT-PCR (Rotor-Gene Q, Qiagen Hilden, Germany) was performed for the detection of IL-1� mRNA containing Maxima� SYBR Green qPCR Master Mix (2X) and all the samples were run in triplicates accompanied by non-template control (NTC). The assay was validated by normalization against reference gene GAPDH and a melt curve was run to ensure standardization. All amplified products of real time PCR were checked on 2% agarose gel for ensuring the correct amplification products. The data was analyzed by  Delta Delta CT  method and the results were furnished as  fold-change (2 (��Ct)) .
Results
Population characteristics
Baseline characteristics of GBC patients and their age and gender matched controls are presented in Table-2. Of the 120 GBC cases, GS patients and 130 healthy controls with complete clinical information and successful genotyping for all the polymorphisms, the mean age was 55.23 � 9.33 years (range, 32-75 years), 49.12 � 16.40 years (range, 18-65 years) and 48.11 � 18.08 (range, 16-75 years)  respectively. The mean age and gender distributions were not significantly different among study groups, suggesting an adequate frequency matching. The possibility of population stratification was ruled out by genomic control method. Gallstones were present in 30% of GBC patients and 44.0% of the GBC patients were associated with tobacco usage in some form. All study patients were incident cases and none of the controls had family history of any inflammation related disorder and cancer.
Association of IL1 gene polymorphisms with GBC
The distribution and statistical analysis of IL-1� +4845G/T, IL1R1 Pst1C/T and IL1R2 Dra111T/G genotypes are shown in Table-3. The observed genotypes for controls were in complete accordance with the Hardy Weinberg equilibrium (p> 0.05). For IL-1� +4845G/T (Figure 1), the genotypic distribution frequency and their alleles revealed no significant association with GBC (OR: 1.08; 95% CI: 0.52-2.27, p = 0.85) or GS disease (OR: 0.75, 95% CI: 0.35-1.60, p = 0.57). Furthermore, this polymorphism showed no significant association with any of the demographic and clinical parameters of the patients (Supplementary Table 1).
For IL1R1 Pst1C/T polymorphism (Figure 2), no significant association was observed with either GBC (OR: 1.34; 95% CI: 0.65-2.79, p= 0.54) or GS disease (OR: 0.80, 95% CI: 0.35-1.82, p =0.68), however the �CT� genotype was observed to be protective and was significantly associated with patient characteristics like rural dwelling (OR: 0.49; 95% CI: 0.26-0.95, p=0.04) and smoking(OR: 0.39; 95% CI: 0.17-0.88, p= 0.02) (Supplementary Table 2).
IL1R2 DraIIIT/G SNP (Figure 3) indicated �GG� genotype and �G� allele to be significantly associated with increased risk of GBC with an odds ratio and p value of 2.65 and 0.011 and 1.57 and 0.014 respectively. However this polymorphism presented no association with GS disease (OR: 1.66, 95% CI: 0.76-3.63, p = 0.23). In correlation with various demographic and clinical features of GBC patients, a significant association was observed with risk factors of GBC including elderly age (OR: 3.05; 95% CI: 1.40-6.62, p= 0.006) and urban dwelling (OR: 4.8; 95% CI: 1.84-12.50, p= 0.001) (Supplementary Table 3).
In the stratification of GBC patients according to the presence or absence of gallstones, none of the polymorphisms was statistically significant (p>0.05) (Table 4).
Haplotype analysis
Sixteen haplotypes of studied IL1 cluster polymorphisms were observed in our population as shown in Table-5. GG/CC/TG haplotype was observed to be highly protective towards GBC (OR=0.07, p=0.028) while towards gallstone disease no significance was observed. Haplotype TT/CT/GG was observed to confer nearly 3-fold and 5-fold risk towards GBC and GS respectively, but the results were statistically insignificant. The frequency of other haplotypes did not differ between the patients and controls.
IL-1� mRNA expression
Relative mRNA expression was analyzed to decipher the role of pro-inflammatory IL-1� in the pathogenesis of GBC. Fold change was calculated for each tumor tissue and finally presented as an average fold change in 30 GB tumor tissues. An average fold change of 0.98 was observed for IL-1� which showed no variation in its mRNA expression in gallbladder tumor tissues as compared to adjacent normal (Figure 4). IL-1� mRNA expression did not differ between tumor and adjacent normal GB tissues.
Statistical analysis
The distribution of the genotypes in controls was compared with that expected from Hardy-Weinberg equilibrium (HWE) by the chi square (�2) test. Odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for age, sex and dwelling were calculated by Fisher�s exact test/Chi square test as appropriate. Students unpaired�t� test was used to compare the mean and standard deviation. All reported p-values were based on two-sided tests. Significance level was taken at p <0.05. Statistical analysis was performed using the software SPSS 23.0 (SPSS Inc., Chicago, Illinois) and Graph Pad Prism version 5.
Discussion
IL1 gene family plays an important role in mediating immune responses. IL-1� is a proinflammatory molecule and its downstream effects are mediated by IL1R1 which is a common receptor of this family.  The IL1R2 is a glycoprotein expressed as a membrane bound and soluble receptor in immune cells particularly monocytes, neutrophills, T and B lymphocytes and acts as a decoy receptor to inhibit proinflammatory activity of IL1R1 receptor. The synergetic role of cytokines in modulating inflammatory responses is well established and emerging evidence suggests that IL-1� which is produced by activated macrophages can induce PTGS2 synthesis, PGE2 release  and  accumulation [38-40] in premalignant lesions that culminates in malignancy by moderating pleiotropic effects like proangiogenesis [41, 42],  antiapoptosis [43, 44] and local immune suppression [45, 46].
GBC is a multifactorial disease and keeping in view the inflammatory inception of GBC, multiple genetic variants of inflammatory genes in combination might be involved during its transformation. Thus to understand the complex etiology of GBC and its associated risk due to gall stones, this study was attempted to achieve a more comprehensive evaluation of GBC risk considering several genetic variants in IL1 gene family simultaneously.
We selected three genes located in the IL1 cluster as candidates for screening. IL-1� which is a proinflammatory cytokine is thought to up-regulate pro-metastatic genes in breast cancer cells and stromal cells [47]. Two SNPs one in the5'UTR regulatory region (-889C>T) and one in exon 5 of this gene (+4845G>T) have been extensively studied and have not shown association with most of the inflammation based cancers [48-50]. However in correlation with GBC and GS disease these polymorphisms have not been studied yet. We genotyped IL-1� +4845 G/T SNP, where presence of T allele results in an Ala to Ser amino acid substitution at residue 114 of the pro-IL-1� molecule which is cleaved between 112 and 113 amino acid residues. This substitution is believed to affect the proteolytic process [23], influence C reactive protein levels in coronary angiography [24] and has been associated with the development of aggressive periodontitis in Chinese males [25].In our study cohort, we did not observe any risk associated with minor allele towards either GBC (OR=1.05, p=0.86) or GS disease (OR=.0.88, p=0.53). Subgroup stratification also revealed IL-1� +4845 SNP to be insignificant towards any clinico-pathological characteristic of patients. In addition, when we analyzed the tissue specific relative mRNA expression of IL-1�, we did not observe its modulated expression in tumor tissues. The expression did not vary with tumor grade or tumor type. IL-1� being a pro inflammatory cytokine has been observed to increase the expression of other potent inflammatory molecules like IL-1� and prostaglandin synthases which have been reported to accumulate in tumor and necrotic tissues [51]. It is possible that IL-1� may trigger the early events in inflammation related cancers by modulating expression of other cytokines while keeping its own concentration at check being an autocrine growth factor [52]. Also IL-1� is believed to be less potent inflammatory cytokine as compared to IL-1� which lies in the same gene cluster. Various studies have substantiated that it is IL-1� but not IL-1� that is involved in long term inflammatory responses and in cancers that are believed to have roots in chronic inflammation [53, 54].
Two key polymorphisms in IL1 receptors were genotyped where we observed IL1R1 Pst1 C/T SNP to be insignificant towards both GBC (p=0.54; OR=1.34; CI= 0.65-2.79) and GS disease (p=0.68; OR=0.80; CI=0.35-1.82). However, on subgroup stratification, the heterozygous �CT� genotype showed protective association with rural dwelling (OR: 0.49, p=0.04), smokers (OR: 0.39, p=0.02) and gall stone absence (OR: 0.46, p=0.017). The TT genotype of this polymorphism has been demonstrated to be associated with decreased percentage of cells expressing IL1R1 on the intact CD14+ monocyte population [55] indicating that this genotype can have a protective function because of lower expression of membrane-bound IL1R1s. In contrast �C� allele of this polymorphism has been demonstrated to be associated with inflammation [56]. Although this SNP was not significant in our population, our study suggests that �T� allele of this SNP might have protective function at least in stratified GBC patient subgroups in our population.
On the other hand, IL1R2 DraIIIT/G polymorphism was observed to be significantly associated with GBC risk. The risk genotype �GG� nearly conferred 3-fold risk towards GBC however no significant risk was observed towards gallstone disease. Among patients with GBC and GS, the frequencies of IL1R2 DraIIIT/G polymorphism TT, GT and GG were 28.3%, 45%, 26.6% and 28.3%, 55%, 16.7% respectively. In case of healthy controls, the frequencies of respective genotypes (TT, GT and GG) were 37%, 50% and 13.1% (Table 3). The �GG� genotype was higher in both GBC and GS patients as compared to healthy controls; however, it reached statistical significance only in case of GBC cases (OR: 2.65, p=0.011). Data stratification on the basis of clinicopathological characteristics of GBC patients revealed a significant association with elderly age group (OR: 3.05, P=0.006), male gender (OR: 1.90, p=0.049) and urban population (OR: 4.8, P=0.001).  IL1R2 DraIIIT/G polymorphism has been observed to have a putative role in the regulation of cell cycle and apoptosis. The presence of �G� allele has been observed to be a possible binding site for transcription factor TATA box binding protein-associated factor (TAF-1) [55]. TAF-1 is required for progression of the cell cycle and has been shown to repress apoptosis in mammalian cells [57]. The TAF-1 protein has intrinsic histone acetyltransferase activity [58] and also binds to and modulates the transcriptional activity of cell cycle proteins [59-61]. Because of the activation of regulatory elements of cell cycle and concurrent repression of apoptosis, GBC patients with underlying GG genotype of this SNP can be more predisposed to tissue necrosis as corroborated by subgroup analysis and a more pronounced inflammatory response which may be an important element in triggering the transformation process of GB tissue. 
Furthermore, the combined effect of three IL1 SNPs on the risk of GBC and GS was investigated by haplotype analysis. The GG/CC/TG combination was observed to be protective towards GBC (OR=0.07, p= 0.028) however none of the haplotypes showed any association with gallstone disease. Our data suggests that these polymorphisms might be in low linkage disequilibrium but there is a possibility that IL1R2 DraIIIT/G also affects GBC susceptibility due to its linkage with any other polymorphism in IL1 gene that reduces its expression which triggers the inflammation process by less inhibition of IL1R1 receptor. 
Conclusion
In conclusion, this case-control study showed that a common variant located in the promoter region of the IL1R2 gene is associated with an increased risk of gall bladder cancer, consistent with the view that chronic inflammation is a key impetus to the carcinogenic transformation in the GB. This study also suggests that the screened variants IL-1� +4845G/T and IL1R1 Pst1 are no prelude to gallstone disease and GB cancer in our population. Further studies are needed that can provide a more comprehensive coverage of genes involved in inflammation-related pathways.
Acknowledgments
We are thankful towards the technical staff of Department of General Surgery, Department of Surgical Gastroenterology and Department of immunology and Molecular Medicine, SKIMS, Srinagar, who helped us in this study.
Funding
The authors gratefully acknowledge the financial support provided by the Department of Biotechnology (DBT, India), vide sanction order no BT/PR7586/12/594/2013).

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How to cite this article: Malik Gawharul Haq, Sabzar A Malik, Imtiyaz A Bhat and Sadaf Ali, et al. �A Significant Association of IL1R2 Draiii T/G Polymorphism with the Risk pf Gall Bladder Cancer in Ethnic Kashmiri Population.� J Mol Biomark Diagn 11 (2020): 441.
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