Association of IL1A, IL1B, and TNF Gene Polymorphisms with Chronic Rhinosinusitis with and Without Nasal Polyposis a Replication Study

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ORIGINAL ARTICLE Association of IL1A, IL1B, and TNF Gene Polymorphisms With Chronic Rhinosinusitis With and Without Nasal Polyposis A Replication Study

Leandra Mfuna Endam, MSc; Chantale Cormier, MD; Yohan Bosse´, PhD; Abdelali Filali-Mouhim, PhD; Martin Desrosiers, MD

Objective: To replicate and extend recent findings in a Main Outcome Measures: Allelic differences be- Turkish population of associations between chronic rhino- tween cases and controls. sinusitis (CRS) with nasal polyposis and single- nucleotide polymorphisms (SNPs) in the IL1A (rs17561 Results: Significant allelic differences between cases and and Ser114Ala), IL1B (rs16944), and TNF (rs361525 and controls were obtained for IL1A rs17561 (odds ratio [OR], rs1800629) genes. 1.48; P=.02). The following 3 additional SNPs in this gene were associated with CRS: rs2856838 (OR, 0.63; P=.003), Design: In a case-control replication study, DNA samples rs2048874 (OR, 0.57; P=.01), and rs1800587 (OR, 1.49; were obtained from 206 patients with severe CRS (cases) P=.02). These 3 SNPs remained significant after correc- and from 196 postal code–matched controls. For IL1A tion for multiple testing. No association was found with and TNF, the 3 reported SNPs were complemented with IL1B or TNF. tagging SNPs using an International HapMap genotyping data set to ensure complete genetic coverage. For IL1B, Conclusions: We replicated the previously reported only the single reported SNP was assessed. A total of 24 association between the IL1A polymorphism and SNPs (7 in IL1A,1inIL1B, and 16 in TNF) were indi- severe CRS and identified 3 potential new associations vidually genotyped. The PLINK software package was used in the same gene. This further supports the potential to perform genetic association tests. contribution of IL1A to the development of CRS. We Setting: Academic research. were unable to replicate previous reports of associations with IL1B or TNF. Patients: Canadian population of individuals with severe CRS. Arch Otolaryngol Head Neck Surg. 2010;136(2):187-192

ENETIC FACTORS ARE BE- cess that is also colonized with nasal and lieved to have an impor- exogenous bacteria, which are believed to tantroleinmanycommon contribute to the disease process.4 Chronic complex disorders. This rhinosinusitis is further subclassified ac- fact, together with the cording to the presence or absence of nasal Author Affiliations: identificationG of many single-nucleotide polyposis. Nasal polyposis is characterized Department of Otolaryngology, polymorphisms (SNPs) throughout the ge- by proliferation of the epithelial layer, glan- Centre de Recherche du Centre nome and the rapidly falling costs of geno- dular hyperplasia, thickening of the basal Hospitalier de l’Universite´de typing, has contributed to the proliferation membrane, edema, focal fibrosis, and cel- Montre´al Hoˆtel-Dieu of association studies in epidemiologic lular infiltration of the stromal layer. In ad- (Ms Mfuna Endam and genetics.1,2 Replication of results of a genetic dition, the inflamed mucosa shows an ac- Drs Cormier, Filali-Mouhim, and Desrosiers), and disease association study in independent cumulation of inflammatory cells, with Department of samples has emerged as a standard for dem- production of numerous proinflammatory Otolaryngology–Head and Neck onstrating the relevance of a candidate gene cytokines.4 Various factors are thought to Surgery, Montreal General for a complex trait.3 influence the severity of inflammatory dis- Hospital, McGill University Chronic rhinosinusitis (CRS) is a com- orders, and it is hypothesized that there is (Dr Desrosiers), Montreal, and mon inflammatory disorder involving the an important genetic component. Genetic Centre de Recherche, Hoˆpital sinus mucosa. Patients with CRS report low factors may affect cytokine gene expres- Laval, Institut Universitaire de Cardiologie et de Pneumologie quality-of-life index values for domains of sion, with repercussions in the severity of 4 5-7 de l’Universite´ Laval, Quebec bodily pain and social functioning. Bi- the inflammatory process. City (Dr Bosse´), Quebec, opsy specimens obtained at the time of sur- Interleukin 1 (IL-1) is a pivotal cyto- Canada. gery demonstrate an inflammatory pro- kine involved in most inflammatory re-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 even drug dependencies.7 Polymorphisms of TNF have Table 1. Clinical Characteristics of Cases and Controls been associated with asthma.14 A 2007 study6 identified IL1A (−4845GT and −4845TT Cases Controls [rs17561]), IL1B (−511CC [rs16944]), and TNF (−238AA Characteristic (n=206) (n=196) [rs361525] and −308GA [rs1800629]) as genotypes that Age, mean (SD), y 52.3 (13.0) 48.8 (15.0) are associated with nasal polyp susceptibility in a co- Male to female ratio 108:98 86:110 hort of 82 Turkish patients with nasal polyposis. In this Race/ethnicity, No. (%)a White 176 (85.4) 175 (89.3) study, we aimed to replicate the CRS associations re- Middle Eastern 10 (4.9) 9 (4.6) corded for IL1A, IL1B, and TNF in a cohort of Canadian Jewish 11 (5.3) 2 (1.0) patients with severe CRS. We further aimed to extend Asian 3 (1.5) 2 (1.0) on these findings by assessing associations across the en- First Nations 3 (1.5) 1 (0.5) tire genes for IL1A and TNF. Black 2 (1.0) 2 (1.0) Hispanic 1 (0.5) 2 (1.0) Pacific Islander 0 3 (1.5) METHODS Initial CRS diagnosis, No. (%) With nasal polyposis 154 (74.8) . . . SUBJECTS Without nasal polyposis 52 (25.2) . . . Age, mean (SD), y A total of 206 patients with severe CRS (with and without na- At first CRS diagnosis 33.4 (14.3) . . . sal polyposis) (hereinafter referred to as cases) and 196 con- At first sinus surgery 38.1 (15.1) . . . trols were recruited prospectively. According to 2004 Ameri- History, No. (%) can Academy of Otolaryngology–Head and Neck Surgery Asthma 131 (63.6) . . . guidelines,15 severe CRS was defined as the following: (1) per- Atopy 135 (65.5) . . . sistent signs or symptoms of CRS despite previous endoscopic Acetylsalicylic acid sensitivity 59 (28.6) . . . sinus surgery or (2) a history of more than 1 endoscopic sinus Smoking . . . surgery procedure for CRS, regardless of outcome. A standard- Nonsmoker 99 (48.1) . . . ized questionnaire was administered assessing age, sex, race/ Ex-smoker 84 (40.8) . . . ethnicity, smoking, seasonal and perennial allergies, physician- Current smoker 23 (11.2) . . . diagnosed asthma, and acetylsalicylic acid intolerance. IgE level Information was recorded about disease-related factors, in- Median (IQR), µg/L 0.087 (0.175) . . . cluding age at diagnosis, age at first sinus surgery, number of Ն0.12 µg/L, No. (%) 86 (41.7) . . . previous surgical procedures, medications required for man- Circulating eosinophils, 3.6 (4.4) . . . median (IQR), % agement of the disease, and assessment of whether the disease was controlled with medication. Initial diagnoses of CRS with Abbreviations: CRS, chronic rhinosinusitis; IQR, interquartile range. or without nasal polyposis were classified. All cases with early- SI conversion factors: To convert IgE level to milligrams per liter, multiply by onset nasal polyposis had previously undergone sweat chlo- 0.001; circulating eosinophils to a proportion of 1.00, multiply by 0.01. ride testing to rule out a diagnosis of cystic fibrosis. aBecause of rounding, percentages may not total 100. Blood samples were collected (BD Vacutainer Serum Sepa- rator Tubes; BD Diagnostics, Franklin Lakes, New Jersey) and sponses. Interleukin 1 is regularly expressed in nasal pol- stored at 4°C until analysis for DNA extraction. Total IgE mea- yps, including epithelial cells and macrophages.7,8 surements were performed (DPC Immulite System; Diagnos- Interleukin 1 activates T cells and monocytes and upregu- tic Products Corporation, Siemens, Los Angeles, California). lates expression of adhesion molecules. Interleukin 1 also Controls were recruited from the following: (1) spouses or nonblood relatives living in the same household as the case or induces expression of numerous cytokines and inflam- (2) individuals recruited by random telephone screening mation-associated proteins, which modulate the cascade matched to the case’s postal code. To minimize differences sec- of inflammatory responses. In humans, IL-1 exists in 2 ondary to potential environmental exposures, the only at- forms, IL-1␣ (IL1A gene [OMIM 147760]) and IL-1␤ (IL1B tempt at matching cases and controls was their geographic lo- gene [OMIM 147720]), located on chromosome 2 in both cation. Nevertheless, a standardized questionnaire assessing age, forms.5 Several studies have demonstrated that polymor- sex, and race/ethnicity was obtained for controls. A kit (Oragene; phisms in IL1A are associated with atopy in adults with- DNA Genotek, Ottawa, Ontario, Canada) was used for saliva out asthma,9 with nasal polyposis in adults with asthma,10 collection and was sent to controls with prepaid return post- and with periodontitis.11 Polymorphisms in IL1B have been age. As recommended by the manufacturer, saliva samples were associated with gastric cancer12 and with inflammatory stored at room temperature until genotyping. 13 The study was approved by McGill University Health Cen- bowel disease. tre and the Centre Hospitalier de l’Universite´ de Montre´alHoˆtel- Tumor necrosis factor (TNF) is a crucial proinflam- Dieu surgical ethics committees. All cases and controls pro- matory cytokine secreted predominantly by mono- vided signed informed consent. cytes, macrophages, and T cells.7 The TNF gene (TNF; OMIM 191160) is located within the highly polymor- DNA EXTRACTION phic major histocompatibility complex region of chromosome 6. It exerts a range of inflammatory and DNA was isolated from peripheral blood leukocytes. Blood was collected in citrate-treated tubes, and DNA was isolated using a immunomodulatory activities that are important in 7 kit (Puregene DNA; Gentra Systems, Germantown, Maryland) ac- host defense. TNF has been putatively implicated in cording to the high-throughput protocol for 10 mL of whole blood the pathogenesis of diverse disease states, including provided with the kit. DNA obtained from saliva was purified per increased susceptibility to infections, autoimmune dis- the manufacturer’s protocol (DNA Genotek). Isolated DNA from orders, neoplasia, neurodegenerative diseases, and blood and saliva was stored at −80°C before use.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 SNP SELECTION AND GENOTYPING Table 2. Single-Nucleotide Polymorphisms (SNPs) Selected To ensure complete coverage of IL1A and TNF, a maximally and Genotyped informative set of SNPs was selected using the Centre d’Etude du Polymorphisme Humain genotype data from the Interna- Minimum Hardy- 16 Allele Weinberg tional HapMap project covering 10 kilobases (kb) upstream SNP Alleles Position Frequency Equilibrium Locationa and downstream for both genes. From this data set, a set of tagging SNPs was selected for each gene using a pairwise tagging IL1A rs17561 GT 113253694 0.28 0.696 Coding algorithm implemented in an available software program nonsynonymous (Haploview, version 3.2; http://www.broadinstitute.org/mpg rs1800587 CT 113259431 0.28 0.608 Untranslated 5 /haploview).17 Minor allele frequency and r2 thresholds were rs2048874 CT 113240438 0.13 0.058 Near gene 5 set at 0.05 and 0.8, respectively. IL1A rs17561 previously iden- rs2856838 CT 113256443 0.40 0.192 Intron tified by Erbek et al6 was force included. For IL1B, genotyping rs3783521 CT 113260048 0.31 0.069 Near gene 5 6 rs3783538 TC 113254666 0.01 1.000 Intron was limited to rs16944 (previously reported ). Overall, we geno- rs6722023 CT 113262338 0.01 1.000 Unknownb typed 7, 1, and 16 SNPs in IL1A, IL1B, and TNF, respectively, for a total of 24 SNPs. IL1B Single-nucleotide polymorphisms were genotyped using a rs16944 GA 113311338 0.33 0.811 Near gene 5 matrix-assisted laser desorption ionization–time-of-flight mass TNF b array spectrometer (Sequenom, San Diego, California). Prim- rs1121800 AT 31643053 0.42 0.085 Unknown rs13211368 GA 31663797 0.02 1.000 Intron ers were designed using available software (SNP Assay De- rs1800629 GA 31651010 0.16 0.332 Near gene 5 sign, version 3.0 for iPLEX reactions; Sequenom). The proto- rs1800750 GA 31650942 0.01 1.000 Near gene 5 col and the reaction condition were in accord with the rs2229094 CT 31648535 0.24 0.474 Missense manufacturer’s instructions. rs2256965 CT 31663109 0.44 0.599 Intron rs2256974 GT 31663371 0.17 0.465 Intron rs2857706 GA 31645585 0.15 0.142 Unknownb STATISTICAL ANALYSIS rs3093561 CT 31655453 0.01 1.000 Near gene 3 rs3093672 CT 31655399 0.02 1.000 Near gene 3 rs361525 GA 31651080 0.03 1.000 Near gene 5 Markers were excluded if they deviated significantly from Hardy- rs4987027 CC 31651073 0.00 1.000 Near gene 5 Weinberg equilibrium (PϽ.01 in controls), if they had low mini- rs769177 GA 31655590 0.04 1.000 Near gene 3 mum allele frequency (Ͻ0.05), or if they had a call rate of less rs7766988 GC 31659326 0.04 0.369 Unknownb than 90% in cases and controls combined. The term call rate is rs9267502 GA 31661173 0.06 0.150 Near gene 5 an indication of the percentage of success of genotyping for a rs9469027 GC 31662693 0.01 1.000 Intron particular SNP and represents the percentage of samples that were a Location data are from the University of California, Santa Cruz successfully genotyped. Odds ratios (ORs) and 95% confidence (http://genome.ucsc.edu/), and from the National Center for Biotechnology intervals (95% CIs) were calculated. Allele, genotype, and hap- Information build 36 (http://www.pubmed.com). lotype frequencies were compared between cases and controls. b No known functional classification. Association analysis was performed by comparing allele frequen- ␹2 cies between cases and controls using the test. To correct for more than 5% eosinophilia. The median total serum IgE multiple testing, we used a method described by Nyholt.18 Logistic regression models were performed using sex as a covariate to cal- level was 0.087 µg/L (to convert IgE level to milligrams culate ORs for homozygous and heterozygous genotypes. All per liter, multiply by 0.001), with 41.7% having IgE lev- association tests and the logistic regression analysis were els of at least 0.12 µg/L. performed using available software (PLINK, version 1.02; http://pngu.mgh.harvard.edu/~purcell/plink/).19 The linkage dis- GENOTYPING ANALYSIS equilibrium plots were visualized using available software (Haploview, version 3.2). All SNPs in IL1A, IL1B, and TNF were successfully Sample size was designed to provide 95% power to detect genotyped (Table 2). Only the SNPs meeting the Ͼ common alleles ( 10%) that confer a 3.0-fold increase in risk. quality control and SNPs with a minimum allele fre- It was also designed to provide 50% power to detect common quency of 0.05 or higher and Hardy-Weinberg equilib- alleles (Ͼ25%) that confer a 2.0-fold increase in risk. rium of PՆ.01 were considered for genetic association tests (Table 3). RESULTS An association with CRS was noted for the following 4 SNPs in IL1A: the previously reported6 rs17561 (OR, 1.48; STUDY PARTICIPANTS P=.02) and 3 other SNPs (rs2856838 [OR, 0.63; P=.003], rs2048874 [OR, 0.57; P=.01], and rs1800587 [OR, 1.49; The clinical characteristics of the study population are P=.02]). Only 3 SNPs (rs2856838, rs2048874, and given in Table 1. The mean (SD) ages of cases and con- rs1800587) remained significant after Nyholt correction for trols were 52.3 (13.0) years and 48.8 (15.0) years, re- multiple testing (PՅ.02). However, for rs17561, we have spectively. For cases, the initial diagnosis was mainly CRS replicated results for the TT homozygote genotype (OR, with nasal polyposis (74.8%). The mean number of pre- 3.39; P=.007). The protective effect of rs2856838 (OR, 0.38; vious surgical procedures was 3.2, with a mean age at first P=.002) and the risk effect of rs1800587 (OR=3.16, sinus surgery of 38.1 years. History of atopy and history P=.008) are enhanced with the homozygote form of the of asthma were present in 65.5% and 63.7%, respec- minor allele. In contrast, no association was found with SNPs tively. Current smoking was present in 11.2%. Mea- in IL1B or TNF (Table 3). sured serum biomarkers showed median circulating eo- Adjustment for sex as a covariate among the 4 signifi- sinophilia of 3.6%, with 33.5% of cases demonstrating cant SNPs in IL1A showed no difference in the risk of

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Minor Case-Control OR (95% CI) P ORHet P ORHom P SNP Allele Frequencies Allelic Model Value (95% CI) Value (95% CI) Value IL1A rs17561 T 0.31-0.24 1.48 (1.06-2.05) .02 1.15 (0.75-1.78) .52 3.39 (1.39-8.27) .007 rs1800587 T 0.32-0.24 1.49 (1.08-2.07) .02 1.19 (0.77-1.84) .42 3.16 (1.35-7.40) .008 rs2048874 T 0.10-0.16 0.57 (0.37-0.89) .01 0.54 (0.32-0.91) .02 0.52 (0.14-1.87) .31 rs2856838 T 0.35-0.46 0.63 (0.47-0.85) .003 0.84 (0.53-1.32) .44 0.38 (0.21-0.70) .002 IL1B rs16944 A 0.33-0.33 0.99 (0.72-1.35) .94 0.97 (0.62-1.50) .88 1.00 (0.50-2.00) Ͼ.99 TNF rs1121800 T 0.41-0.43 0.94 (0.70-1.26) .67 1.01 (0.63-1.61) .97 0.84 (0.44-1.59) .59 rs1800629 A 0.16-0.16 1.01 (0.68-1.50) .98 1.05 (0.65-1.68) .86 0.90 (0.28-2.86) .86 rs2229094 C 0.24-0.24 1.04 (0.74-1.46) .83 1.29 (0.84-1.99) .24 0.61 (0.23-1.63) .32 rs2256965 T 0.46-0.43 1.11 (0.83-1.49) .49 1.03 (0.65-1.65) .89 1.26 (0.69-2.31) .45 rs2256974 T 0.17-0.18 0.92 (0.62-1.34) .65 0.96 (0.60-1.52) .85 0.74 (0.24-2.27) .60 rs2857706 A 0.15-0.14 1.10 (0.72-1.67) .66 1.15 (0.71-1.84) .57 0.88 (0.12-6.31) .90 rs9267502 A 0.07-0.06 1.18 (0.64-2.18) .98 1.13 (0.58-2.20) .73 1.74 (0.16-19.4) .65

Abbreviations: CI, confidence interval; OR, odds ratio; ORHet, odds ratio for heterozygotes; ORHom, odds ratio for homozygotes.

chr2

11 3250 kb Genotyped SNPs

Entrez genes NM_000575

IL1A: interleukin 1

Figure. Linkage disequilibrium plot of the IL1A gene. The shade of squares illustrates the strength of pairwise r 2 values; black indicates perfect linkage disequilibrium (r 2=1.00), and white indicates perfect equilibrium (r 2=0.00). The r 2 linkage disequilibrium value is indicated within each square. Single-nucleotide polymorphisms (SNPs) not in Hardy-Weinberg equilibrium or with low minimum allele frequency are excluded. chr2 indicates chromosome 2; Entrez, Entrez Gene database; and kb, kilobases. In the interest of space, percentage is expressed as a rs17561 value from 0 to 100 rather than as the corresponding decimal value. rs2048874 rs2856838 rs1800587

Block 1 (18 kb) 1245

52526 22 96 5

CRS. Assessment of association of these SNPs in the popu- ary to underlying asthma and is not limited to the sub- lation showed no increase in the strength of the associa- group having CRS with nasal polyposis. tion for the subgroups with nasal polyposis or asthma, The linkage disequilibrium pattern for IL1A in our confirming that the observed relationship is not second- population is shown in the Figure. Strong linkage dis-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 equilibrium is noted between rs17561 and rs1800587 should guide us toward more effective treatment and (r2=0.96), indicating that the SNPs represent the same screening for this inflammatory disease. association signal. Two haplotypes that included these 2 SNPs and whose frequencies in cases were statistically Submitted for Publication: April 20, 2009; final revi- different from those in controls are GTC (P=.002) and sion received July 17, 2009; accepted September 1, TCT (P=.01). 2009. Correspondence: Martin Desrosiers, MD, Department of Otolaryngology, Centre de Recherche du Centre Hospi- COMMENT talier de l’Universite´ de Montre´al Hoˆtel-Dieu, 3840 Rue St-Urbain, Montreal, QB H2W 1T8, Canada (desrosiers Our objective was to replicate results from a previous [email protected]). study6 showing association between IL1A, IL1B,and Author Contributions: Ms Mfuna Endam and Dr TNF polymorphisms and CRS with nasal polyposis. In Cormier contributed equally to this work. Ms Mfuna this study, we confirm the association between IL1A Endam and Dr Desrosiers had full access to all the rs17561 and CRS and extend these results by identify- data in the study and take responsibility for the integ- ing 3 additional IL1A SNPs associated with CRS. How- rity of the data and the accuracy of the data analysis. ever, we did not replicate previously reported6 associa- Study concept and design: Mfuna Endam, Cormier, tions of IL1B and TNF polymorphisms with CRS. Bosse´, Filali-Mouhim, and Desrosiers. Acquisition of Although we have replicated the association, the data: Mfuna Endam, Cormier, and Desrosiers. Analysis means by which the rs17561 polymorphism contrib- and interpretation of data: Mfuna Endam, Cormier, utes to the development of disease remains unex- Bosse´, Filali-Mouhim, and Desrosiers. Drafting of the plained. Because rs17561 represents a nonsynony- manuscript: Mfuna Endam and Desrosiers. Critical mous mutation (Ser114Ala), this may lead to an revision of the manuscript for important intellectual con- altered protein with a potential functional effect in tent: Cormier, Bosse´, Filali-Mouhim, and Desrosiers. CRS. Statistical analysis: Filali-Mouhim. Obtained funding: We also report the following 3 new SNPs not previ- Desrosiers. Administrative, technical, and material sup- ously associated with CRS: rs1800587, rs2048874, and port: Mfuna Endam, Cormier, and Desrosiers. Study rs2856838. Located in the promoter, rs1800587 is supervision: Mfuna Endam, Bosse´, and Desrosiers. in tight linkage disequilibrium with rs17561. In a Financial Disclosure: None reported. Brazilian population, rs1800587 has also been associ- Funding/Support: This study was supported by the Fon- ated with chronic periodontal disease.11 To the best of dation Antoine Turmel (Dr Desrosiers). Dr Bosse´ is a re- our knowledge, IL1A rs2048874 and rs2856838 have search scholar from the Heart and Stroke Foundation of not previously been associated with CRS or other Canada. diseases. Previous Presentation: This study was presented at the In this study, IL1B rs16944 was not associated with 2009 Annual Meeting of the American Academy of Al- severe CRS or nasal polyposis. A lack of association of lergy, Asthma, and Immunology; March 15, 2009; Wash- this SNP in IL1B was reported in another study10 con- ington, DC. ducted among a Finnish population with nasal polyp- Additional Contributions: We thank the research phy- osis and asthma. sicians, students, and assistants for sample and data col- Although Erbek et al6 showed that TNF (−238 lections. McGill University, Universite´ de Montre´al, and [rs361525] and −308 [rs1800629]) was associated with Genome Quebec Innovation Centre provided assistance susceptibility to nasal polyposis, TNF polymorphisms were and expertise throughout the conception and develop- not associated with CRS in our study. The AA genotype ment of the entire genetics of CRS effort. for rs361525 associated with CRS in the Turkish popu- 6 lation was not found in our population. REFERENCES TNF has been associated with several inflammatory 14 20 diseases, including asthma, atopy, and chronic ob- 1. Cordell HJ, Clayton DG. 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