0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Proinflammatory Cytokine Single Nucleotide Polymorphisms in Nasal Polyposis FREE

Selim S. Erbek, MD; Erkan Yurtcu, PhD; Seyra Erbek, MD; F. Belgin Atac, PhD; Feride I. Sahin, MD, PhD; Ozcan Cakmak, MD
[+] Author Affiliations

Author Affiliations: Departments of Otolaryngology (Drs S. S. Erbek, S. Erbek, and Cakmak) and Medical Biology and Genetics (Drs Yurtcu, Atac, and Sahin), Faculty of Medicine, Baskent University, Ankara, Turkey.


Arch Otolaryngol Head Neck Surg. 2007;133(7):705-709. doi:10.1001/archotol.133.7.705.
Text Size: A A A
Published online

Objective  To investigate the association between nasal polyposis (NP) and single nucleotide polymorphisms of the proinflammatory cytokines IL (interleukin) 1α (the IL1A gene), IL-1β (the IL1B gene), and tumor necrosis factor α (the TNFA gene).

Design  Prospective case-control trial.

Setting  Tertiary referral center.

Patients  Eighty-two patients with NP and 106 healthy volunteers without sinonasal disease.

Main Outcome Measures  Genotypes of IL1A (4845G, 4845T), IL1B (–511C, –511T) and TNFA (–238G, –238A and –308G, –308A) were identified by restriction fragment length polymorphism analyses after polymerase chain reaction.

Results  The 4845 GT and 4845 TT genotypes of the IL1A gene were associated with NP (P < .05). The frequency of the –511 CC genotype of the IL1B gene was significantly higher in patients with NP than in controls (P = .01). The frequency of the –511 CT genotype of IL1B was significantly higher (P = .01) in the controls than in the patients with NP. The –238 AA genotype of the TNFA gene was higher in the patients with NP than in the controls (P = .05). There was a significantly high risk of susceptibility to NP in patients with the –308 GA genotype of TNFA (P = .001). None of the genotypes of the proinflammatory cytokines were related to sex, the presence of atopy, asthma, or aspirin intolerance (P > .05).

Conclusion  The IL1A (4845 GT and 4845 TT), IL1B (–511 CC), and TNFA (–238 AA and –308 GA) genotypes were associated with susceptibility to NP in our study population.

Nasal polyposis (NP), a chronic disease of the nasal and paranasal sinus mucosa, is characterized by proliferation of the epithelial layer, glandular hyperplasia, thickening of the basement membrane, edema, focal fibrosis, and cellular infiltration of the stromal layer.1 Nasal polyposis is frequently associated with asthma and aspirin intolerance. Recent studies of the underlying mechanism of NP strongly suggest that it is a multifactorial disease with several etiologic factors. Chronic persistent inflammation is undoubtedly a major factor in the development of NP, regardless of its underlying cause. Polyp tissue includes mixed inflammatory cells, of which eosinophils are the most dominant; they have the primary role in the perpetuation of chronic inflammation. However, polyp tissue eosinophilia is an entity independent of atopy. Wei et al2 suggested that eosinophils more often migrate to nasal tissue in patients with chronic sinusitis than in controls. They concluded that research should focus on eosinophil activation and chemotaxis pathways.2

Tumor necrosis factor α (TNF-α) and IL (interleukin) 1 are members of the proinflammatory cytokine gene family; they are produced by various cells, including epithelial cells and macrophages. Those cytokines act synergistically in the process of chronic inflammation. Tumor necrosis factor α and IL-1 regulate the extravasation of eosinophils into the lamina propria by up-regulating adhesion molecule expression in nasal polyps.3

The delicate balance between proinflammatory and anti-inflammatory cytokines may regulate the inflammatory reaction in NP as it does in other infectious diseases. It has been suggested that various genetic and epigenetic factors modify the severity of chronic inflammatory diseases.4 Among the genetic factors, single nucleotide polymorphisms (SNPs) or microsatellite polymorphisms (particularly those within the regulatory regions of genes that code for cytokines) often affect expression levels and can serve as disease modifiers.

Interleukin 1, a pleotrophic cytokine that is produced in response to pathogenic infection, is a well-established mediator of chronic inflammatory disease. In humans, the IL-1 cytokine gene family consists of 3 genes located on the long arm of chromosome 2 that encode for the IL-1α, IL-1β, and the IL-1 receptor antagonist. There are 2 variants in the IL1A gene (at sites −889 and 4845 [both C→T and in linkage disequilibrium]). Three SNPs in the IL1B gene have been described; 2 of them are located in the promoter region (−511 and −31 [both C→T]), and the other is in the coding region (3954C, 3954T).4,5 Those transitions affect the level of IL-1 expression in response to various stimuli, and their presence has been associated with a variety of immune and chronic inflammatory diseases. Karjalainen et al6 investigated the association of IL1A and IL1B genotypes with NP. However, their study was limited to patients with asthma.

The TNFA gene is located on human chromosome 6 between HLA-B and HLA-DR within the class III region of the major histocompatibility complex.7 Among the reported polymorphisms defined in the TNFA gene, promoter polymorphisms at positions −238 and −308 are the best characterized and have been shown to influence the production of protein at the transcriptional level. As discussed by Haukim et al,4 there have been several recent studies that reported the association of TNFA (−238G, −238A and −308G, −308A) polymorphisms with certain chronic diseases, including asthma. Recently, the association of the TNFA genotype and simple NP without allergy or aspirin intolerance was reported by Fajardo-Dolci et al8; however, they could not define the association between simple NP and TNFA (−238G, −238A and −308G, −308A) polymorphisms in their study population. In view of the location and proposed biologic effect of TNF-α and IL-1, we thought that it would be prudent to further evaluate the association between TNFA (−238G, −238A and −308G, −308A), IL1A (4845G, 4845T), and IL1B (−511C, −511T) polymorphisms and NP. We also investigated whether the genotypes of the proinflammatory cytokines mentioned in this section were related to presence of allergy, asthma, or aspirin intolerance in patients with NP.

A prospective study was conducted with 82 consecutive patients with NP. The diagnosis of NP was based on each patient's medical history and on the results of nasal endoscopy and computed tomography. Diagnoses of asthma or the acetylsalicylic acid triad (aspirin intolerance, asthma, and nasal polyposis) were based on the patients' medical history and examinations in the department of pulmonology. The presence of an antrochoanal polyp, cystic fibrosis, or an inverted papilloma were the exclusion criteria. The control group consisted of 106 healthy volunteers (65 men, 41 women; mean [SD] age, 45.1 [12.6] years) without sinonasal disease. All participants provided written informed consent, and the ethics committee of Baskent University, Ankara, Turkey, approved the study protocol.

Polyp size was classified on a 0 to 3 scale as described by Lildholdt et al.9 The results of paranasal sinus computed tomography were staged according to the Lund and Mackay staging system.10 Skin prick tests were performed on all patients. Each patient was evaluated for sensitivity to 18 common allergen extracts (ALK Abello, Madrid, Spain) and to positive and negative control substances. A test result was considered positive for sensitivity when at least 1 of the induration diameters was 3 mm higher than that in the negative control. Serum total IgE values, which were determined by means of the chemiluminescent immunoassay method, and serum total eosinophil counts were also obtained.

GENOTYPING

Peripheral blood samples were drawn from all participants. Genomic DNA (hereinafter, DNA) was extracted from peripheral blood leukocytes by means of a high pure polymerase chain reaction (PCR) template preparation kit (Roche Diagnostics GmbH, Mannheim, Germany). Genotypes of IL1A (4845G, 4845T), IL1B (−5111C, −5111T), and TNFA (−238G, −238A and −308G, −308A) were determined by restriction fragment length polymorphism analyses after PCR with appropriate primers according to the slightly modified procedures previously described.8,11

The 4845G, 4845T polymorphism of the IL1A gene was identified after digestion with the restriction enzyme SatI, which yielded 124–, 76–, and 29–base pair (bp) bands in the presence of allele G, as well as 153- and 76-bp bands in the presence of allele A.

The IL1B (−511C, −511T) polymorphism was identified after digestion with AvaI, which yielded 305-bp bands in the presence of allele C, as well as 190- and 115-bp bands in the presence of allele T.

To detect the −238G, −238A polymorphism of the TNFA gene, a 152-bp PCR product was cut with MspI. The uncut product (152 bp) showed the presence of the A allele. If the PCR product was cut into 2 fragments (as 132 and 20 bp), it revealed the G allele.

A 220-bp PCR product was cut with NcoI to reveal the TNFA −308A, −308G polymorphism. The uncut product (220 bp) showed the presence of the A allele. If the PCR product was cut into 2 fragments (as 201 and 19 bp), it revealed the G allele.

STATISTICAL EVALUATION

Calculations were performed with SPSS (version 11.0; SSPS Inc, Chicago, Illinois) and MINITAB (version 13.0; Minitab Inc, State College, Pennsylvania) statistical software. Cytokine genotypes in the patients with NP and in the controls were compared by means of the Pearson χ2 test, χ2 test, and 2-proportion z score. The χ2 test was also used to evaluate association of atopy, sex, and polyp size with cytokine genotypes in patients with NP. The 1-way analysis of variance test was used to correlate the presence of blood eosinophilia, total IgE levels, and the results of computed tomography with cytokine genotypes in the patients with NP.

Of the 82 patients with NP, 53 (65%) were men and 29 (35%) were women (mean [SD] age, 45.23 [11.77] years; range, 19-78 years). The diagnoses were NP in 55 patients, NP with asthma in 15, and NP with aspirin-induced asthma in 12. The clinical characteristics of the patients are shown in Table 1.

Table Graphic Jump LocationTable 1. Clinical Characteristics of Subjects With Nasal Polyposis a

The genotypes did not differ according to the sex of the subjects (> .05). There were no differences in any of the genotypes of IL1A, IL1B, or TNFA when patients with only NP were compared with those who had concomitant asthma or aspirin-induced asthma (P > .05). The cytokine genotypes cited were not associated with atopy, blood eosinophilia, or total IgE level (P > .05).

The frequency of the IL1A GG genotype was significantly higher in controls than in patients with NP (< .001). The 4845 GT and 4845 TT genotypes of the IL1A gene were found to be highly associated with NP (P < .001 and P = .05, respectively), and the susceptibility to NP was markedly increased (common odds ratio, 2.743; P < .001) in these patients. These findings were associated with the higher frequency of the T allele in patients with NP vs controls (P < .001). On the one hand, the frequency of the –511 CC genotype of the IL1B gene was significantly higher in patients with NP than in controls (P = .01). On the other hand, the −511 CT genotype frequency of IL1B was significantly higher in the controls than in the patients with NP (P = .01) (Table 2). However, the IL1B −511 TT genotype was similar in both groups (P > .05).

Table Graphic Jump LocationTable 2. Genotypes and Allele Frequencies of the IL1A Gene (4845G, 4845T) and the IL1B Gene (−511C, −511T) in Subjects With Nasal Polyposis (NP) and in Controls

The frequencies of the –238 GG and –238 GA genotypes of the TNFA gene were similar in patients with NP and in controls (Table 3). However, the –238 AA genotype of the TNFA gene was significantly higher in patients with NP than in controls (P = .05). The frequency of the –308 GG genotype of the TNFA gene did not differ in controls vs patients with NP (P > .05). The risk of susceptibility to NP was significantly higher in patients with NP who had a –308 GA genotype of TNFA than in controls (P < .001) (Table 3). However, distribution of the –308 AA genotype of TNFA was significantly higher in the control group than in patients with NP (P = .004).

Table Graphic Jump LocationTable 3. Genotypes and Allele Frequencies of the TNFA Gene (−238G, −238A and −308G, −308A) in Subjects With Nasal Polyposis (NP) and in Controls

Neither the polyp size nor the results of CT (P > .05) were associated with the studied proinflammatory cytokine gene polymorphisms.

Most of the changes in the inflammation can be triggered by the activities of TNF-α and IL-1; many of their functions are shared, especially those leading to the amplification of immunologic and inflammatory processes. In this preliminary study, we identified 4 functional polymorphisms (TNFA –238G, –238A and –308G, –308A; IL1A 4845G, 4845T; and IL1B –511C, –511T) in 2 proinflammatory cytokine genes. Those polymorphisms are thought to be related to the inflammatory pathway in NP. Therefore, we examined their potential association with the development of NP. In our series of patients, IL1A (4845 GT and 4845 TT), IL1B (–511 CC), and TNFA (−238 AA and –308 GA) genotypes were associated with susceptibility to NP. None of the genotypes of those cytokines were related to sex, the presence of atopy, asthma, or aspirin intolerance (P > .05). Moreover, the genotypes were not associated with polyp size, sinus opacification, blood eosinophilia, or total IgE level (P > .05).

Interleukin 1 is highly associated with chronic airway disease. The IL1A 4845 GT and 4845 TT genotypes were associated with NP in our series of patients. Moreover, the frequency of the IL1A 4845 GG genotype was significantly higher in our control subjects than that in the subjects with NP (P < .001). This finding contradicts those reported by Karjalainen et al,6 in which IL1A was defined as a specific gene locus and the 4845 GG genotype was identified as an important susceptibility factor for NP in patients with asthma. We found no association between cytokine genotypes and asthma or aspirin-induced asthma in patients with NP. Thus, we concluded that 4845T allele (either in heterozygote or homozygote) of the IL1A gene was solely associated with NP in our series of patients representing the Turkish population. In contrast to other SNPs reported in this study, the IL1A 4845G, 4845T polymorphism is found in the coding region of the gene, and it is in close proximity to a protease cleavage site wherein a calpainlike protease cleaves between amino acids 112 and 113 that convert pro–IL-1α to a mature cytokine. Therefore, the amino acid alteration at residue 114 from alanin to serine may exert an effect owing to the change in the hydrophobisity index of the protein, which is required for the enzymatic efficiency of the protease during the cleavage process. Therefore, it may cause resistance during the conversion of pro–IL-1α to IL-1α that may trigger the fibrotic cascade.

Interleukin 1β is the primary secreted form of IL-1. The cellular effect of a high level of IL-1 may trigger the inflammatory process in NP via stimulation of the synthesis of other inflammatory proteins and/or adhesion molecules. One of the 2 polymorphisms defined in the promoter region of the IL1B gene is −511C, −511T. The increased local production of IL-1β is pronounced in –511 TT carriers.12 The activity of IL-1β has been proposed to play a role in the development of asthma and some other chronic airway diseases as well.13 Recently, Karjalainen et al6 reported the lack of association between IL1B −511C, −511T and NP. In our study, the −511 CC genotype was associated with the NP phenotype (P = .01). Hence, the existence of the heterozygote T allele at this position had a protective effect against NP (P = .01). This finding can be seen as contradictory to the cellular effect of the –511 TT genotype. There may be 2 possible explanations for this result. First, −31C, −31T is the second polymorphism located in the promoter region of IL1B where the T allele is the first base of the TATA box. The allelic interaction between the −511 and −31 polymorphic sites may determine the overall strength of the IL1B promoter. Second, the strong linkage disequilibrium defined among markers of the IL1A-IL1B-IL1-RN genes has led investigators to search for predisposing loci within the highly polymorphic IL1 gene cluster instead of a single loci.14 Therefore the IL-1 system may act in concert to determine an overall inflammatory phenotype, the identification of which may help to pinpoint molecular markers of both NP susceptibility and outcome.1517

Tumor necrosis factor α stimulates the production of oxygen metabolites that cause toxic cell injury. Data implicate the role of TNF-α in airway remodeling and fibrosis.18 This evidence suggests that the TNF-α level may be a determinant of pathogenesis and disease progression in NP. Because the TNF response to infection is partly regulated at the transcriptional level, TNFA promoter polymorphisms have been the subject of intense interest as potential determinants of disease susceptibility. In a recent report, SNPs in the promoter regions of TNFA (−238 and −308) did not show statistically significant differences between the control group and patients with simple NP.8 We identified a statistically significant association between the −238 AA genotype of TNFA and NP (P < .05). This finding probably emphasizes the role of elevated TNF-α level in inflammation. As reported previously,18 the −238 A allele of the TNFA gene results in increased transcriptional activity. The TNFA repressor site has been identified between −254 and −230 in the TNFA promoter. The increased transcriptional activity might result from a G to A substitution by decreasing the binding of a transcriptional repressor or by enhancing the binding of an activator of transcription by changing the DNA conformation.

The more commonly studied promoter polymorphism of the TNFA gene is at the 308 nucleotide upstream of the transcription start site (G −308A). Tumor necrosis factor α promoter activity is higher when the −308 nucleotide is adenosine because transcription factors preferentially bind to this nucleotide.11 In our study, we could not define a statistically significant association between the −308 AA genotype of TNFA and NP. However, the risk of susceptibility to NP was significantly increased in patients with the −308 GA genotype of the TNFA gene (P < .001). Wilson et al19 reported that the −308 GA genotype of the TNFA gene showed an increased TNF-α level when compared with that of subjects with G homozygotes. All of these findings underline the importance of elevated TNF-α level in triggering the inflammation, but the TNFA gene itself may not be the only factor in determining TNF-α level. Evident data strongly indicate that a TNFA gene polymorphism might contribute to histocompatibility complex associations. It has been reported20 that the polymorphism of the TNFA gene is linked with the HLA haplotype. Moreover, a polymorphic site in the TNFB gene was reported as another molecular determinant of TNF-α production.21 As a result, taking into consideration all reports, the linkage of the 2 TNF genes (TNFA and TNFB) with histocompatibility complex polymorphisms may be responsible for interindividual differences in TNF-α production. Further molecular studies are required to test this hypothesis.

In conclusion, IL1A (4845 GT and 4845 TT), IL1B (−511 CC), and TNFA (−238 AA and −308 GA) genotypes were associated with susceptibility to NP in our series of patients representing the Turkish population. Despite this, it may be possible that other known, or as yet unknown, SNPs within these genes could still be important in the pathogenesis of NP (ie, haplotyping of all the SNPs in a candidate gene may be positive). With this in mind, further research is needed to explore the usefulness of cytokine gene polymorphisms as markers of disease susceptibility (and for risk stratification) and to define their precise role in the pathogenesis of NP. In doing so, areas for therapeutic intervention using population-based treatment strategies, such as use of monoclonal antibodies, might be successfully implemented.

Correspondence: Selim S. Erbek, MD, Department of Otolaryngology, Baskent University Konya Teaching and Research Center, Saray Caddesi No. 1, Selcuklu Konya, Turkey (selimerbek@gmail.com).

Submitted for Publication: December 14, 2006; final revision received March 12, 2007; accepted March 14, 2007.

Author Contributions: Drs S. S. Erbek, Yurtcu, S. Erbek, Atac, Sahin, and Cakmak 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: S. S. Erbek, S. Erbek, Sahin, and Cakmak. Acquisition of data: S. S. Erbek, Yurtcu, S. Erbek, and Atac. Analysis and interpretation of data: S. S. Erbek and Sahin. Drafting of the manuscript: S. S. Erbek, Yurtcu, S. Erbek, and Atac. Critical revision of the manuscript for important intellectual content: Atac, Sahin, and Cakmak. Statistical analysis: Yurtcu. Obtained funding: Yurtcu and Atac. Study supervision: Atac, Sahin, and Cakmak.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Baskent University Research Fund (project No. KA05/22).

Additional Contributions: Ayse Canan Yazici, PhD, contributed to the statistical analysis; Tendu Gozkaya, BSc, provided excellent technical assistance; and Mehri Demiratan assisted with blood sampling.

Lee  JYLee  SHLee  HM  et al.  Analysis of gene expression profiles of normal human nasal mucosa and nasal polyp tissues by SAGE. J Allergy Clin Immunol 2006;118 (1) 134- 142
PubMed Link to Article
Wei  JLKita  HSherris  DAKern  EBWeaver  APonikau  JU The chemotactic behavior of eosinophils in patients with chronic rhinosinusitis. Laryngoscope 2003;113 (2) 303- 306
PubMed Link to Article
Bernstein  JM Update on the molecular biology of nasal polyposis. Otolaryngol Clin North Am 2005;38 (6) 1243- 1255
PubMed Link to Article
Haukim  NBidwell  JLKeen  L  et al.  Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 2002;3 (6) 313- 330
PubMed Link to Article
Chakravorty  MGhosh  AChoudhury  ASantra  AHembrum  JRoychoudhury  S Interaction between IL1B gene promoter polymorphisms in determining susceptibility to Helicobacter pylori associated duodenal ulcer. Hum Mutat 2006;27 (5) 411- 419
PubMed Link to Article
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 Link to Article
Carroll  MCKatzman  PAlicot  EM  et al.  Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci U S A 1987;84 (23) 8535- 8539
PubMed Link to Article
Fajardo-Dolci  GSolorio-Abreu  JRomero-Alverez  JC  et al.  DQA1 and DQB1 association and nasal polyposis. Otolaryngol Head Neck Surg 2006;135 (2) 243- 247
PubMed Link to Article
Lildholdt  TRundcrantz  HBende  MLarsen  K Glucocorticoid treatment for nasal polyps: the use of topical budesonide powder, intramuscular betamethasone, and surgical treatment. Arch Otolaryngol Head Neck Surg 1997;123 (6) 595- 600
PubMed Link to Article
Lund  VJMackay  IS Staging in rhinosinusitus. Rhinology 1993;31 (4) 183- 184
PubMed
Shiau  MYWu  CYHuang  CNHu  SWLin  SJChang  YH TNF-alpha polymorphisms and type 2 diabetes mellitus in Taiwanese patients. Tissue Antigens 2003;61 (5) 393- 397
PubMed Link to Article
Mark  LLHaffajee  ADSocransky  SS  et al.  Effect of the interleukin-1 genotype on monocyte IL-1beta expression in subjects with adult periodontitis. J Periodontal Res 2000;35 (3) 172- 177
PubMed Link to Article
Müller  B Cytokine imbalance in non-immunological chronic disease. Cytokine 2002;18 (6) 334- 339
PubMed Link to Article
Smith  AJPKeen  LJBillinghan  MJ  et al.  Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A, IL1B-IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 2004;5 (6) 451- 460
PubMed Link to Article
Hurme  MSanttila  S IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol 1998;28 (8) 2598- 2602
PubMed Link to Article
Cox  ACamp  NJNicklin  MJHdi Giovine  FSDuff  GW An analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a novel grouping method for multiallelic markers. Am J Hum Genet 1998;621180- 1188
PubMed Link to Article
Abecasis  GRNoguchi  EAndrea  H  et al.  Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001;68 (1) 191
PubMed Link to Article
Hajeer  AHHutchinson  IV Influence of TNFα gene polymorphisms on TNFα production and disease. Hum Immunol 2001;62 (11) 1191- 1199
PubMed Link to Article
Wilson  AGSymons  JAMcDowell  TLMcDevitt  HODuff  GW Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997;94 (7) 3195- 3199
PubMed Link to Article
Gallagher  GEskdale  JOh  HHRichards  SDCampbell  DAField  M Polymorphisms in the TNF gene cluster and MHC serotypes in the West of Scotland. Immunogenetics 1997;45 (3) 188- 194
PubMed Link to Article
Heesen  MKunz  DBachmann-Mennenga  BMerk  HFBloemeke  B Linkage disequilibrium between tumor necrosis factor (TNF)-alpha-308 G/A promoter and TNF-beta NcoI polymorphisms: association with TNF-alpha response of granulocytes to endotoxin stimulation. Crit Care Med 2003;31211- 214
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical Characteristics of Subjects With Nasal Polyposis a
Table Graphic Jump LocationTable 2. Genotypes and Allele Frequencies of the IL1A Gene (4845G, 4845T) and the IL1B Gene (−511C, −511T) in Subjects With Nasal Polyposis (NP) and in Controls
Table Graphic Jump LocationTable 3. Genotypes and Allele Frequencies of the TNFA Gene (−238G, −238A and −308G, −308A) in Subjects With Nasal Polyposis (NP) and in Controls

References

Lee  JYLee  SHLee  HM  et al.  Analysis of gene expression profiles of normal human nasal mucosa and nasal polyp tissues by SAGE. J Allergy Clin Immunol 2006;118 (1) 134- 142
PubMed Link to Article
Wei  JLKita  HSherris  DAKern  EBWeaver  APonikau  JU The chemotactic behavior of eosinophils in patients with chronic rhinosinusitis. Laryngoscope 2003;113 (2) 303- 306
PubMed Link to Article
Bernstein  JM Update on the molecular biology of nasal polyposis. Otolaryngol Clin North Am 2005;38 (6) 1243- 1255
PubMed Link to Article
Haukim  NBidwell  JLKeen  L  et al.  Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 2002;3 (6) 313- 330
PubMed Link to Article
Chakravorty  MGhosh  AChoudhury  ASantra  AHembrum  JRoychoudhury  S Interaction between IL1B gene promoter polymorphisms in determining susceptibility to Helicobacter pylori associated duodenal ulcer. Hum Mutat 2006;27 (5) 411- 419
PubMed Link to Article
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 Link to Article
Carroll  MCKatzman  PAlicot  EM  et al.  Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci U S A 1987;84 (23) 8535- 8539
PubMed Link to Article
Fajardo-Dolci  GSolorio-Abreu  JRomero-Alverez  JC  et al.  DQA1 and DQB1 association and nasal polyposis. Otolaryngol Head Neck Surg 2006;135 (2) 243- 247
PubMed Link to Article
Lildholdt  TRundcrantz  HBende  MLarsen  K Glucocorticoid treatment for nasal polyps: the use of topical budesonide powder, intramuscular betamethasone, and surgical treatment. Arch Otolaryngol Head Neck Surg 1997;123 (6) 595- 600
PubMed Link to Article
Lund  VJMackay  IS Staging in rhinosinusitus. Rhinology 1993;31 (4) 183- 184
PubMed
Shiau  MYWu  CYHuang  CNHu  SWLin  SJChang  YH TNF-alpha polymorphisms and type 2 diabetes mellitus in Taiwanese patients. Tissue Antigens 2003;61 (5) 393- 397
PubMed Link to Article
Mark  LLHaffajee  ADSocransky  SS  et al.  Effect of the interleukin-1 genotype on monocyte IL-1beta expression in subjects with adult periodontitis. J Periodontal Res 2000;35 (3) 172- 177
PubMed Link to Article
Müller  B Cytokine imbalance in non-immunological chronic disease. Cytokine 2002;18 (6) 334- 339
PubMed Link to Article
Smith  AJPKeen  LJBillinghan  MJ  et al.  Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A, IL1B-IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 2004;5 (6) 451- 460
PubMed Link to Article
Hurme  MSanttila  S IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol 1998;28 (8) 2598- 2602
PubMed Link to Article
Cox  ACamp  NJNicklin  MJHdi Giovine  FSDuff  GW An analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a novel grouping method for multiallelic markers. Am J Hum Genet 1998;621180- 1188
PubMed Link to Article
Abecasis  GRNoguchi  EAndrea  H  et al.  Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001;68 (1) 191
PubMed Link to Article
Hajeer  AHHutchinson  IV Influence of TNFα gene polymorphisms on TNFα production and disease. Hum Immunol 2001;62 (11) 1191- 1199
PubMed Link to Article
Wilson  AGSymons  JAMcDowell  TLMcDevitt  HODuff  GW Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997;94 (7) 3195- 3199
PubMed Link to Article
Gallagher  GEskdale  JOh  HHRichards  SDCampbell  DAField  M Polymorphisms in the TNF gene cluster and MHC serotypes in the West of Scotland. Immunogenetics 1997;45 (3) 188- 194
PubMed Link to Article
Heesen  MKunz  DBachmann-Mennenga  BMerk  HFBloemeke  B Linkage disequilibrium between tumor necrosis factor (TNF)-alpha-308 G/A promoter and TNF-beta NcoI polymorphisms: association with TNF-alpha response of granulocytes to endotoxin stimulation. Crit Care Med 2003;31211- 214
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 33

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles