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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 FREE

Leandra Mfuna Endam, MSc; Chantale Cormier, MD; Yohan Bossé, PhD; Abdelali Filali-Mouhim, PhD; Martin Desrosiers, MD
[+] Author Affiliations

Author Affiliations: Department of Otolaryngology, Centre de Recherche du Centre Hospitalier de l’Université de Montréal Hôtel-Dieu (Ms Mfuna Endam and Drs Cormier, Filali-Mouhim, and Desrosiers), and Department of Otolaryngology–Head and Neck Surgery, Montreal General Hospital, McGill University (Dr Desrosiers), Montreal, and Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l’Université Laval, Quebec City (Dr Bossé), Quebec, Canada.


Arch Otolaryngol Head Neck Surg. 2010;136(2):187-192. doi:10.1001/archoto.2009.219.
Text Size: A A A
Published online

Objective  To replicate and extend recent findings in a Turkish population of associations between chronic rhinosinusitis (CRS) with nasal polyposis and single-nucleotide polymorphisms (SNPs) in the IL1A (rs17561 and Ser114Ala), IL1B (rs16944), and TNF (rs361525 and rs1800629) genes.

Design  In a case-control replication study, DNA samples were obtained from 206 patients with severe CRS (cases) and from 196 postal code–matched controls. For IL1A and TNF, the 3 reported SNPs were complemented with tagging SNPs using an International HapMap genotyping data set to ensure complete genetic coverage. For IL1B, only the single reported SNP was assessed. A total of 24 SNPs (7 in IL1A, 1 in IL1B, and 16 in TNF) were individually genotyped. The PLINK software package was used to perform genetic association tests.

Setting  Academic research.

Patients  Canadian population of individuals with severe CRS.

Main Outcome Measures  Allelic differences between cases and controls.

Results  Significant allelic differences between cases and controls were obtained for IL1A rs17561 (odds ratio [OR], 1.48; P = .02). The following 3 additional SNPs in this gene were associated with CRS: rs2856838 (OR, 0.63; P = .003), rs2048874 (OR, 0.57; P = .01), and rs1800587 (OR, 1.49; P = .02). These 3 SNPs remained significant after correction for multiple testing. No association was found with IL1B or TNF.

Conclusions  We replicated the previously reported association between the IL1A polymorphism and severe CRS and identified 3 potential new associations in the same gene. This further supports the potential contribution of IL1A to the development of CRS. We were unable to replicate previous reports of associations with IL1B or TNF.

Figures in this Article

Genetic factors are believed to have an important role in many common complex disorders. This fact, together with the identification of many single-nucleotide polymorphisms (SNPs) throughout the genome and the rapidly falling costs of genotyping, has contributed to the proliferation of association studies in epidemiologic genetics.1,2 Replication of results of a genetic disease association study in independent samples has emerged as a standard for demonstrating the relevance of a candidate gene for a complex trait.3

Chronic rhinosinusitis (CRS) is a common inflammatory disorder involving the sinus mucosa. Patients with CRS report low quality-of-life index values for domains of bodily pain and social functioning.4 Biopsy specimens obtained at the time of surgery demonstrate an inflammatory process that is also colonized with nasal and exogenous bacteria, which are believed to contribute to the disease process.4 Chronic rhinosinusitis is further subclassified according to the presence or absence of nasal polyposis. Nasal polyposis is characterized by proliferation of the epithelial layer, glandular hyperplasia, thickening of the basal membrane, edema, focal fibrosis, and cellular infiltration of the stromal layer. In addition, the inflamed mucosa shows an accumulation of inflammatory cells, with production of numerous proinflammatory cytokines.4 Various factors are thought to influence the severity of inflammatory disorders, and it is hypothesized that there is an important genetic component. Genetic factors may affect cytokine gene expression, with repercussions in the severity of the inflammatory process.57

Interleukin 1 (IL-1) is a pivotal cytokine involved in most inflammatory responses. Interleukin 1 is regularly expressed in nasal polyps, including epithelial cells and macrophages.7,8 Interleukin 1 activates T cells and monocytes and upregulates expression of adhesion molecules. Interleukin 1 also induces expression of numerous cytokines and inflammation-associated proteins, which modulate the cascade of inflammatory responses. In humans, IL-1 exists in 2 forms, IL-1α (IL1A gene [OMIM 147760]) and IL-1β (IL1B gene [OMIM 147720]), located on chromosome 2 in both forms.5 Several studies have demonstrated that polymorphisms in IL1A are associated with atopy in adults without asthma,9 with nasal polyposis in adults with asthma,10 and with periodontitis.11 Polymorphisms in IL1B have been associated with gastric cancer12 and with inflammatory bowel disease.13

Tumor necrosis factor (TNF) is a crucial proinflammatory cytokine secreted predominantly by monocytes, macrophages, and T cells.7 The TNF gene (TNF; OMIMg 191160) is located within the highly polymorphic major histocompatibility complex region of chromosome 6. It exerts a range of inflammatory and immunomodulatory activities that are important in host defense.7TNF has been putatively implicated in the pathogenesis of diverse disease states, including increased susceptibility to infections, autoimmune disorders, neoplasia, neurodegenerative diseases, and even drug dependencies.7 Polymorphisms of TNF have been associated with asthma.14

A 2007 study6 identified IL1A (−4845GT and −4845TT [rs17561]]), IL1B (−511CC [ rs16944]]), and TNF (−238AA [rs361525] and −308GA [rs1800629]) as genotypes that are associated with nasal polyp susceptibility in a cohort of 82 Turkish patients with nasal polyposis. In this study, we aimed to replicate the CRS associations recorded for IL1A, IL1B, and TNF in a cohort of Canadian patients with severe CRS. We further aimed to extend on these findings by assessing associations across the entire genes for IL1A and TNF.

SUBJECTS

A total of 206 patients with severe CRS (with and without nasal polyposis) (hereinafter referred to as cases) and 196 controls were recruited prospectively. According to 2004 American Academy of Otolaryngology–Head and Neck Surgery guidelines,15 severe CRS was defined as the following: (1) persistent signs or symptoms of CRS despite previous endoscopic sinus surgery or (2) a history of more than 1 endoscopic sinus surgery procedure for CRS, regardless of outcome. A standardized questionnaire was administered assessing age, sex, race/ethnicity, smoking, seasonal and perennial allergies, physician-diagnosed asthma, and acetylsalicylic acid intolerance. Information was recorded about disease-related factors, including age at diagnosis, age at first sinus surgery, number of previous surgical procedures, medications required for management of the disease, and assessment of whether the disease was controlled with medication. Initial diagnoses of CRS with or without nasal polyposis were classified. All cases with early-onset nasal polyposis had previously undergone sweat chloride testing to rule out a diagnosis of cystic fibrosis.

Blood samples were collected (BD Vacutainer Serum Separator Tubes; BD Diagnostics, Franklin Lakes, New Jersey) and stored at 4°C until analysis for DNA extraction. Total IgE measurements were performed (DPC Immulite System; Diagnostic Products Corporation, Siemens, Los Angeles, California).

Controls were recruited from the following: (1) spouses or nonblood relatives living in the same household as the case or (2) individuals recruited by random telephone screening matched to the case's postal code. To minimize differences secondary to potential environmental exposures, the only attempt at matching cases and controls was their geographic location. Nevertheless, a standardized questionnaire assessing age, sex, and race/ethnicity was obtained for controls. A kit (Oragene; DNA Genotek, Ottawa, Ontario, Canada) was used for saliva collection and was sent to controls with prepaid return postage. As recommended by the manufacturer, saliva samples were stored at room temperature until genotyping.

The study was approved by McGill University Health Centre and the Centre Hospitalier de l’Université de Montréal Hôtel-Dieu surgical ethics committees. All cases and controls provided signed informed consent.

DNA EXTRACTION

DNA was isolated from peripheral blood leukocytes. Blood was collected in citrate-treated tubes, and DNA was isolated using a kit (Puregene DNA; Gentra Systems, Germantown, Maryland) according to the high-throughput protocol for 10 mL of whole blood provided with the kit. DNA obtained from saliva was purified per the manufacturer's protocol (DNA Genotek). Isolated DNA from blood and saliva was stored at −80°C before use.

SNP SELECTION AND GENOTYPING

To ensure complete coverage of IL1A and TNF, a maximally informative set of SNPs was selected using the Centre d’Etude du Polymorphisme Humain genotype data from the International HapMap project16 covering 10 kilobases (kb) upstream and downstream for both genes. From this data set, a set of tagging SNPs was selected for each gene using a pairwise tagging algorithm implemented in an available software program (Haploview, version 3.2; http://www.broadinstitute.org/mpg/haploview).17 Minor allele frequency and r2 thresholds were set at 0.05 and 0.8, respectively. IL1A rs17561 previously identified by Erbek et al6 was force included. For IL1B, genotyping was limited to rs16944 (previously reported6). Overall, we genotyped 7, 1, and 16 SNPs in IL1A, IL1B, and TNF, respectively, for a total of 24 SNPs.

Single-nucleotide polymorphisms were genotyped using a matrix-assisted laser desorption ionization–time-of-flight mass array spectrometer (Sequenom, San Diego, California). Primers were designed using available software (SNP Assay Design, version 3.0 for iPLEX reactions; Sequenom). The protocol and the reaction condition were in accord with the manufacturer's instructions.

STATISTICAL ANALYSIS

Markers were excluded if they deviated significantly from Hardy-Weinberg equilibrium (P < .01 in controls), if they had low minimum allele frequency (<0.05), or if they had a call rate of less than 90% in cases and controls combined. The term call rate is an indication of the percentage of success of genotyping for a particular SNP and represents the percentage of samples that were successfully genotyped. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Allele, genotype, and haplotype frequencies were compared between cases and controls. Association analysis was performed by comparing allele frequencies between cases and controls using the χ2 test. To correct for multiple testing, we used a method described by Nyholt.18 Logistic regression models were performed using sex as a covariate to calculate ORs for homozygous and heterozygous genotypes. All association tests and the logistic regression analysis were performed using available software (PLINK, version 1.02; http://pngu.mgh.harvard.edu/~purcell/plink/).19 The linkage disequilibrium plots were visualized using available software (Haploview, version 3.2).

Sample size was designed to provide 95% power to detect common alleles (>10%) that confer a 3.0-fold increase in risk. It was also designed to provide 50% power to detect common alleles (>25%) that confer a 2.0-fold increase in risk.

STUDY PARTICIPANTS

The clinical characteristics of the study population are given in Table 1. The mean (SD) ages of cases and controls were 52.3 (13.0) years and 48.8 (15.0) years, respectively. For cases, the initial diagnosis was mainly CRS with nasal polyposis (74.8%). The mean number of previous surgical procedures was 3.2, with a mean age at first sinus surgery of 38.1 years. History of atopy and history of asthma were present in 65.5% and 63.7%, respectively. Current smoking was present in 11.2%. Measured serum biomarkers showed median circulating eosinophilia of 3.6%, with 33.5% of cases demonstrating more than 5% eosinophilia. The median total serum IgE level was 0.087 μg/L (to convert IgE level to milligrams per liter, multiply by 0.001), with 41.7% having IgE levels of at least 0.12 μg/L.

Table Graphic Jump LocationTable 1. Clinical Characteristics of Cases and Controls
GENOTYPING ANALYSIS

All SNPs in IL1A, IL1B, and TNF were successfully genotyped (Table 2). Only the SNPs meeting the quality control and SNPs with a minimum allele frequency of 0.05 or higher and Hardy-Weinberg equilibrium of P ≥ .01 were considered for genetic association tests (Table 3).

Table Graphic Jump LocationTable 2. Single-Nucleotide Polymorphisms (SNPs) Selected and Genotyped
Table Graphic Jump LocationTable 3. Association of IL1A, IL1B, and TNF With Chronic Rhinosinusitis

An association with CRS was noted for the following 4 SNPs in IL1A: the previously reported6 rs17561 (OR, 1.48; P = .02) and 3 other SNPs (rs2856838 [OR, 0.63; P = .003], rs2048874 [OR, 0.57; P = .01], and rs1800587 [OR, 1.49; P = .02]). Only 3 SNPs (rs2856838, rs2048874, and rs1800587) remained significant after Nyholt correction for multiple testing (P ≤ .02). However, for rs17561, we have replicated results for the TT homozygote genotype (OR, 3.39; P = .007). The protective effect of rs2856838 (OR, 0.38; P = .002) and the risk effect of rs1800587 (OR = 3.16, P = .008) are enhanced with the homozygote form of the minor allele. In contrast, no association was found with SNPs in IL1B or TNF (Table 3).

Adjustment for sex as a covariate among the 4 significant SNPs in IL1A showed no difference in the risk of CRS. Assessment of association of these SNPs in the population showed no increase in the strength of the association for the subgroups with nasal polyposis or asthma, confirming that the observed relationship is not secondary to underlying asthma and is not limited to the subgroup having CRS with nasal polyposis.

The linkage disequilibrium pattern for IL1A in our population is shown in the Figure. Strong linkage disequilibrium is noted between rs17561 and rs1800587 (r2 = 0.96), indicating that the SNPs represent the same association signal. Two haplotypes that included these 2 SNPs and whose frequencies in cases were statistically different from those in controls are GTC (P = .002) and TCT (P = .01).

Place holder to copy figure label and caption
Figure.

Linkage disequilibrium plot of the IL1A gene. The shade of squares illustrates the strength of pairwise r2 values; black indicates perfect linkage disequilibrium (r2 = 1.00), and white indicates perfect equilibrium (r2 = 0.00). The r2 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 value from 0 to 100 rather than as the corresponding decimal value.

Graphic Jump Location

Our objective was to replicate results from a previous study6 showing association between IL1A, IL1B, and TNF polymorphisms and CRS with nasal polyposis. In this study, we confirm the association between IL1A rs17561 and CRS and extend these results by identifying 3 additional IL1A SNPs associated with CRS. However, we did not replicate previously reported6 associations of IL1B and TNF polymorphisms with CRS.

Although we have replicated the association, the means by which the rs17561 polymorphism contributes to the development of disease remains unexplained. Because rs17561 represents a nonsynonymous mutation (Ser114Ala), this may lead to an altered protein with a potential functional effect in CRS.

We also report the following 3 new SNPs not previously associated with CRS: rs1800587, rs2048874, and rs2856838. Located in the promoter, rs1800587 is in tight linkage disequilibrium with rs17561. In a Brazilian population, rs1800587 has also been associated with chronic periodontal disease.11 To the best of our knowledge, IL1A rs2048874 and rs2856838 have not previously been associated with CRS or other diseases.

In this study, IL1B rs16944 was not associated with severe CRS or nasal polyposis. A lack of association of this SNP in IL1B was reported in another study10 conducted among a Finnish population with nasal polyposis and asthma.

Although Erbek et al6 showed that TNF (−238 [rs361525] and −308 [rs1800629]) was associated with susceptibility to nasal polyposis, TNF polymorphisms were not associated with CRS in our study. The AA genotype for rs361525 associated with CRS in the Turkish population6 was not found in our population.

TNF has been associated with several inflammatory diseases, including asthma,14 atopy,20 and chronic obstructive pulmonary disease.21 However, these results have not been confirmed in other studies.2225 The lack of reproducibility may be ascribed to small sample sizes, biologic and phenotypic complexity, population-specific linkage disequilibrium, effect size bias, or population stratification.3

In conclusion, our data confirm a previous study6 implicating an IL1A polymorphism and nasal polyposis. We identify 3 additional IL1A SNPs associated with CRS. One of them (rs1800587) is in tight linkage disequilibrium with the previously reported SNP (rs17561). No association with the disease was observed for SNPs in IL1B or TNF.

Understanding the role of IL1A will take us a step further in our understanding of the pathogenesis of CRS and should guide us toward more effective treatment and screening for this inflammatory disease.

Correspondence: Martin Desrosiers, MD, Department of Otolaryngology, Centre de Recherche du Centre Hospitalier de l’Université de Montréal Hôtel-Dieu, 3840 Rue St-Urbain, Montreal, QB H2W 1T8, Canada (desrosiers_martin@hotmail.com).

Submitted for Publication: April 20, 2009; final revision received July 17, 2009; accepted September 1, 2009.

Author Contributions: Ms Mfuna Endam and Dr Cormier contributed equally to this work. Ms Mfuna Endam and Dr Desrosiers had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mfuna Endam, Cormier, Bossé, Filali-Mouhim, and Desrosiers. Acquisition of data: Mfuna Endam, Cormier, and Desrosiers. Analysis and interpretation of data: Mfuna Endam, Cormier, Bossé, Filali-Mouhim, and Desrosiers. Drafting of the manuscript: Mfuna Endam and Desrosiers. Critical revision of the manuscript for important intellectual content: Cormier, Bossé, Filali-Mouhim, and Desrosiers. Statistical analysis: Filali-Mouhim. Obtained funding: Desrosiers. Administrative, technical, and material support: Mfuna Endam, Cormier, and Desrosiers. Study supervision: Mfuna Endam, Bossé, and Desrosiers.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Fondation Antoine Turmel (Dr Desrosiers). Dr Bossé is a research scholar from the Heart and Stroke Foundation of Canada.

Previous Presentation: This study was presented at the 2009 Annual Meeting of the American Academy of Allergy, Asthma, and Immunology; March 15, 2009; Washington, DC.

Additional Contributions: We thank the research physicians, students, and assistants for sample and data collections. McGill University, Université de Montréal, and Genome Quebec Innovation Centre provided assistance and expertise throughout the conception and development of the entire genetics of CRS effort.

Cordell  HJClayton  DG Genetic association studies. Lancet 2005;366 (9491) 1121- 1131
PubMed
Pennisi  E Breakthrough of the year: human genetic variation. Science 2007;318 (5858) 1842- 1843
PubMed
Ioannidis  JPNtzani  EETrikalinos  TAContopoulos-Ioannidis  DG Replication validity of genetic association studies. Nat Genet 2001;29 (3) 306- 309
PubMed
Fokkens  WLund  VMullol  JEuropean Position Paper on Rhinosinusitis and Nasal Polyps Group, EP3OS 2007: European position paper on rhinosinusitis and nasal polyps 2007: a summary for otorhinolaryngologists. Rhinology 2007;45 (2) 97- 101
PubMed
Haukim  NBidwell  JLSmith  AJ  et al.  Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 2002;3 (6) 313- 330
PubMed
Erbek  SSYurtcu  EErbek  SAtac  FBSahin  FICakmak  O Proinflammatory cytokine single nucleotide polymorphisms in nasal polyposis. Arch Otolaryngol Head Neck Surg 2007;133 (7) 705- 709
PubMed
Otto  BAWenzel  SE The role of cytokines in chronic rhinosinusitis with nasal polyps. Curr Opin Otolaryngol Head Neck Surg 2008;16 (3) 270- 274
PubMed
Hamaguchi  YSuzumura  HArima  SSakakura  Y Quantitation and immunocytological identification of interleukin-1 in nasal polyps from patients with chronic sinusitis. Int Arch Allergy Immunol 1994;104 (2) 155- 159
PubMed
Karjalainen  JHulkkonen  JPessi  T  et al.  The IL1A genotype associates with atopy in nonasthmatic adults. J Allergy Clin Immunol 2002;110 (3) 429- 434
PubMed
Karjalainen  JJoki-Erkkila  VPHulkkonen  J  et al.  The IL1A genotype is associated with nasal polyposis in asthmatic adults. Allergy 2003;58 (5) 393- 396
PubMed
Moreira  PRCosta  JEGomez  RSGollob  KJDutra  WO The IL1A (−889) gene polymorphism is associated with chronic periodontal disease in a sample of Brazilian individuals. J Periodontal Res 2007;42 (1) 23- 30
PubMed
Machado  JCPharoah  PSousa  S  et al.  Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology 2001;121 (4) 823- 829
PubMed
Meisenzahl  EMRujescu  DKirner  A  et al.  Association of an interleukin-1β genetic polymorphism with altered brain structure in patients with schizophrenia. Am J Psychiatry 2001;158 (8) 1316- 1319
PubMed
Thomas  PS Tumour necrosis factor-α: the role of this multifunctional cytokine in asthma. Immunol Cell Biol 2001;79 (2) 132- 140
PubMed
Meltzer  EOHamilos  DLHadley  JA  et al. American Academy of Allergy, Asthma and Immunology; American Academy of Otolaryngic Allergy; American Academy of Otolaryngology–Head and Neck Surgery; American College of Allergy, Asthma and Immunology; American Rhinologic Society, Rhinosinusitis: establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131 (6) ((suppl)) S1- S62
PubMed
International HapMap Consortium, A haplotype map of the human genome. Nature 2005;437 (7063) 1299- 1320
PubMed
Barrett  JCFry  BMaller  JDaly  MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21 (2) 263- 265
PubMed
Nyholt  DR A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004;74 (4) 765- 769
PubMed
Purcell  SNeale  BTodd-Brown  K  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81 (3) 559- 575
PubMed
Castro  JTelleria  JJLinares  PBlanco-Quiros  A Increased TNFA*2, but not TNFB*1, allele frequency in Spanish atopic patients. J Investig Allergol Clin Immunol 2000;10 (3) 149- 154
PubMed
Sakao  STatsumi  KIgari  HShino  YShirasawa  HKuriyama  T Association of tumor necrosis factor α gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163 (2) 420- 422
PubMed
Takeuchi  KMajima  YSakakura  Y Tumor necrosis factor gene polymorphism in chronic sinusitis. Laryngoscope 2000;110 (10, pt 1) 1711- 1714
PubMed
Louis  RLeyder  EMalaise  MBartsch  PLouis  E Lack of association between adult asthma and the tumour necrosis factor α–308 polymorphism gene. Eur Respir J 2000;16 (4) 604- 608
PubMed
Zhu  SChan-Yeung  MBecker  AB  et al.  Polymorphisms of the IL-4, TNF-α, and Fcα RIβ genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med 2000;161 (5) 1655- 1659
PubMed
Teramoto  SIshii  T No association of tumor necrosis factor-α gene polymorphism and COPD in Caucasian smokers and Japanese smokers. Chest 2001;119 (1) 315- 316
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Linkage disequilibrium plot of the IL1A gene. The shade of squares illustrates the strength of pairwise r2 values; black indicates perfect linkage disequilibrium (r2 = 1.00), and white indicates perfect equilibrium (r2 = 0.00). The r2 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 value from 0 to 100 rather than as the corresponding decimal value.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Cases and Controls
Table Graphic Jump LocationTable 2. Single-Nucleotide Polymorphisms (SNPs) Selected and Genotyped
Table Graphic Jump LocationTable 3. Association of IL1A, IL1B, and TNF With Chronic Rhinosinusitis

References

Cordell  HJClayton  DG Genetic association studies. Lancet 2005;366 (9491) 1121- 1131
PubMed
Pennisi  E Breakthrough of the year: human genetic variation. Science 2007;318 (5858) 1842- 1843
PubMed
Ioannidis  JPNtzani  EETrikalinos  TAContopoulos-Ioannidis  DG Replication validity of genetic association studies. Nat Genet 2001;29 (3) 306- 309
PubMed
Fokkens  WLund  VMullol  JEuropean Position Paper on Rhinosinusitis and Nasal Polyps Group, EP3OS 2007: European position paper on rhinosinusitis and nasal polyps 2007: a summary for otorhinolaryngologists. Rhinology 2007;45 (2) 97- 101
PubMed
Haukim  NBidwell  JLSmith  AJ  et al.  Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 2002;3 (6) 313- 330
PubMed
Erbek  SSYurtcu  EErbek  SAtac  FBSahin  FICakmak  O Proinflammatory cytokine single nucleotide polymorphisms in nasal polyposis. Arch Otolaryngol Head Neck Surg 2007;133 (7) 705- 709
PubMed
Otto  BAWenzel  SE The role of cytokines in chronic rhinosinusitis with nasal polyps. Curr Opin Otolaryngol Head Neck Surg 2008;16 (3) 270- 274
PubMed
Hamaguchi  YSuzumura  HArima  SSakakura  Y Quantitation and immunocytological identification of interleukin-1 in nasal polyps from patients with chronic sinusitis. Int Arch Allergy Immunol 1994;104 (2) 155- 159
PubMed
Karjalainen  JHulkkonen  JPessi  T  et al.  The IL1A genotype associates with atopy in nonasthmatic adults. J Allergy Clin Immunol 2002;110 (3) 429- 434
PubMed
Karjalainen  JJoki-Erkkila  VPHulkkonen  J  et al.  The IL1A genotype is associated with nasal polyposis in asthmatic adults. Allergy 2003;58 (5) 393- 396
PubMed
Moreira  PRCosta  JEGomez  RSGollob  KJDutra  WO The IL1A (−889) gene polymorphism is associated with chronic periodontal disease in a sample of Brazilian individuals. J Periodontal Res 2007;42 (1) 23- 30
PubMed
Machado  JCPharoah  PSousa  S  et al.  Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology 2001;121 (4) 823- 829
PubMed
Meisenzahl  EMRujescu  DKirner  A  et al.  Association of an interleukin-1β genetic polymorphism with altered brain structure in patients with schizophrenia. Am J Psychiatry 2001;158 (8) 1316- 1319
PubMed
Thomas  PS Tumour necrosis factor-α: the role of this multifunctional cytokine in asthma. Immunol Cell Biol 2001;79 (2) 132- 140
PubMed
Meltzer  EOHamilos  DLHadley  JA  et al. American Academy of Allergy, Asthma and Immunology; American Academy of Otolaryngic Allergy; American Academy of Otolaryngology–Head and Neck Surgery; American College of Allergy, Asthma and Immunology; American Rhinologic Society, Rhinosinusitis: establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131 (6) ((suppl)) S1- S62
PubMed
International HapMap Consortium, A haplotype map of the human genome. Nature 2005;437 (7063) 1299- 1320
PubMed
Barrett  JCFry  BMaller  JDaly  MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21 (2) 263- 265
PubMed
Nyholt  DR A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004;74 (4) 765- 769
PubMed
Purcell  SNeale  BTodd-Brown  K  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81 (3) 559- 575
PubMed
Castro  JTelleria  JJLinares  PBlanco-Quiros  A Increased TNFA*2, but not TNFB*1, allele frequency in Spanish atopic patients. J Investig Allergol Clin Immunol 2000;10 (3) 149- 154
PubMed
Sakao  STatsumi  KIgari  HShino  YShirasawa  HKuriyama  T Association of tumor necrosis factor α gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163 (2) 420- 422
PubMed
Takeuchi  KMajima  YSakakura  Y Tumor necrosis factor gene polymorphism in chronic sinusitis. Laryngoscope 2000;110 (10, pt 1) 1711- 1714
PubMed
Louis  RLeyder  EMalaise  MBartsch  PLouis  E Lack of association between adult asthma and the tumour necrosis factor α–308 polymorphism gene. Eur Respir J 2000;16 (4) 604- 608
PubMed
Zhu  SChan-Yeung  MBecker  AB  et al.  Polymorphisms of the IL-4, TNF-α, and Fcα RIβ genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med 2000;161 (5) 1655- 1659
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