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Increased Prevalence of Interleukin-1 Receptor Antagonist Gene Polymorphism in Patients With Chronic Rhinosinusitis

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ORIGINAL ARTICLE

Increased Prevalence of Interleukin-1 Receptor

Antagonist Gene Polymorphism in Patients

With Chronic Rhinosinusitis

Yuan-Kai Cheng, MD; Chia-Der Lin, MD; Weng-Cheng Chang, MD, PhD; Guang-Yuh Hwang, PhD; Shih-Wei Tsai, PhD; Lei Wan, PhD; Ming-Hsui Tsai, MD; Jeffrey J. P. Tsai, PhD; Fuu-Jen Tsai, MD, PhD

Objective:To assess the association of the interleukin (IL)-1␤ and the IL-1 receptor antagonist (IL-1Ra) gene polymorphisms with chronic rhinosinusitis (CRS). Design:Genotyping of the 2 IL-1␤ gene (IL1B) poly-morphisms (promoter and exon) and the IL-1Ra gene (IL1RN) polymorphism (intron 2) was performed using polymerase chain reaction and restriction length frag-ment polymorphism analyses.

Setting: Prospective study, tertiary medical center. Patients:The study population comprised 88 consecu-tive adult Taiwan-Chinese patients who met stringent cri-teria for CRS and received endoscopic sinus surgery and 103 healthy volunteers of the same ethnicity and similar age range. Of the 88 patients, 61 had CRS with nasal pol-yps, while the other 27 had CRS without nasal polyps.

Results:There were significant differences in the dis-tribution of the IL1RN polymorphism between the con-trol subjects and patients with CRS (P⬍.05). The II al-lele of IL1RN occurred more frequently in the CRS patient group, and the odds ratio for subjects with I/II genotype was 3.39 (95% confidence interval, 1.25-9.18). In the case of CRS without nasal polyps, the odds ratio for subjects with I/II genotype was further increased to 4.75 (1.39-16.25). There was no association between the other 2 poly-morphisms of IL1B and CRS.

Conclusion: Increased prevalence of IL1RN phism in patients with CRS suggests that this polymor-phism, or a polymorphism in linkage disequilibrium with it, may be involved in the development of CRS. Arch Otolaryngol Head Neck Surg. 2006;132:285-290

C

HRONIC RHINOSINUSITIS

(CRS) is defined as “a condition manifested by a n i n f l a m m a t o r y r e -sponse involving the mu-cous membranes of the nasal cavity and paranasal sinuses, fluids within these cavi-ties, and/or underlying bone”1; it carries a significant personal and economic bur-den and is accompanied by decreased pro-ductivity and impaired quality of life.2,3 Various models involving physiological and anatomical factors have been pro-posed to explain the etiology of this preva-lent disease. Nevertheless, the cause and pathogenesis remain controversial.3-6More recently, the role of chronic inflamma-tory processes in the pathogenesis of CRS has been increasingly recognized.1,3-5The histopathologic features of CRS is char-acterized by thickening of the basement membrane, subepithelial fibrosis and edema, goblet cell hyperplasia, and per-sistent inflammation.7However, many re-ports of familial clustering of sinus dis-ease implicate a genetic basis for CRS that

is resistant to medical and surgical inter-vention. There is increasing evidence that both inflammatory and genetic factors may be involved in the development of CRS.8-10 Interleukin (IL)-1, one of the most im-portant proinflammatory cytokines, is a po-tent transmitter between cells during in-flammatory reactions.11Interleukin-1␤ as well as tumor necrosis factor (TNF) were reported to up-regulate the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which enhances leukocyte in-filtration into the nasal mucosa.12The genes in the 1 complex code for 3 proteins, IL-1␣, IL-1␤, and IL-1 receptor antagonist (IL-1Ra). In contrast to the␣ form, the IL-1␤ molecule is mainly secreted by the cells, and its plasma levels are often elevated in vari-ous diseases.13Different polymorphisms have been described in the IL-1␤ gene (IL1B), and at least 2 of them are known to influence protein production: one is located within the promoter region at po-sition -511 and the other in exon 5.14 More-over, the IL-1␤ gene is situated on chro-Author Affiliations:

Departments of Otolaryngology (Drs Cheng, Lin, Chang, and M.-H. Tsai) and Medical Research (Drs Wan and F.-J. Tsai), China Medical University Hospital, Taichung, Taiwan; Department of Life Science, Tunghai University, Taichung (Drs Cheng and Hwang); Institute of

Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan (Dr S.-W. Tsai); and Department of Biotechnology and Bioinformatics, Asia University, Taichung (Dr J.J.P. Tsai).

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mosome 2 in close linkage with another gene of the IL-1 gene family that encodes for IL-1Ra. Linkage disequilib-rium of the IL-1␤ and IL-1Ra genes during recombina-tion may be one of the causes of the disease.15Interleukin 1Ra, the natural competitive inhibitor of IL-1, also plays an important role as a regulator of inflammation by oc-cupying the IL-1 cell surface receptor.16There are 5 vari-able number tandem repeated polymorphisms in intron 2 of the IL-1Ra gene (IL1RN).17The I, II, III, IV, and V al-leles correspond to 4, 2, 5, 3, and 6 copies of the 86–base pair repeated sequence, respectively. The variants of I and II allele of IL1RN are associated with altered production rates of IL-1Ra protein and may influence the variation of the intracellular signal pathway.13,18

Polymorphisms of the IL-1 genes have been shown to be associated with several inflammatory diseases, such as sepsis, rheumatoid arthritis, and asthma.19-22 Believ-ing that individuals with greater inflammatory re-sponses may be more susceptible to inflammatory dis-ease, we investigated whether there is an association between chronic rhinosinusitis and 2 polymorphisms in the IL-1␤ gene (promoter and exon 5) and 1 polymor-phism in the IL-1Ra gene (intron 2).

METHODS

PATIENTS

The study population comprised 88 consecutive patients with a clinical diagnosis of CRS who underwent endoscopic sinus

surgery by the senior authors (Y.-K.C., C.-D.L., and M.-H.T.) at China Medical University Hospital, Taichung, Taiwan, be-tween July 2002 and December 2003. All patients received a thorough medical history taking and serial rhinologic exami-nations, including endoscopy and computed tomographic (CT) scan; patients with nasal diseases other than CRS or with a high index of suspicion for gastroesophageal reflux were excluded from our study.

The diagnosis of CRS was based on its definition by the American Academy of Otolaryngology–Head and Neck Sur-gery, which describes the typical symptoms that persist for 12 weeks or longer, and positive findings on CT scan showing opaci-fication or swelling of the ethmoidal and maxillary mucosa and an obstruction of the ostiomeatal complex bilaterally but with-out polyp formation visible by preoperative nasal endoscopy or during surgery.1Bilateral nasal polyps were diagnosed based on history, clinical examination, nasal endoscopy, and sinus CT scan. Nasal polyposis was defined as presence of endo-scopically visible bilateral polyps growing from the middle na-sal meatus into the nana-sal cavities and affecting bilaterally more than 1 paranasal sinus according to the CT scan. Of the 88 pa-tients, 61 were diagnosed as having CRS with nasal polyps and the remaining 27 as having CRS without nasal polyps (Table 1). The allergic status was evaluated based on the measure-ment of serum total IgE level and the allergy screening test Pha-diatop (Pharmacia CAP System, Uppsala, Sweden).22,23Total serum IgE levels and Phadiatop findings were analyzed by the fluoroenzyme immunoassay method in an accredited labora-tory according to the manufacturer’s instructions (Pharmacia CAP System). Subjects were considered nonatopic if they did not have Phadiatop positivity and had a serum IgE level lower than 100 IU/mL. Nonatopic subjects had negative skin test re-sults and were symptom free.24,25In this context, 51 of the pa-tients with CRS showed a negative result for atopy and were substratified as CRS patients without allergy (nonatopic).

The 88 enrolled adult Taiwanese patients (31 women and 57 men) ranged in age from 18 to 73 years, with a mean ± SD age of 43.8 ± 17.1 years; all patients were unrelated and had re-calcitrant CRS without evidence of fungal infection, cystic fi-brosis, or mucociliary disorders. The 103 CRS-free, unrelated control volunteers (44 women and 59 men) were from the same area as study group members and ranged in age from 20 to 70 years, with a mean ± SD age of 38 ± 12.8 years; all of them were examined by the same physician in the same fashion, includ-ing IgE serology, CT scan, and endoscopy. This study was re-viewed by the institutional review board of the China Medical University Hospital. Informed consent was obtained from all patients who participated in this study.

GENOTYPING

We investigated 3 gene polymorphisms, IIL1B promoter (−511 C→T substitution), IL1B exon (⫹3953 C→T substitution) and IL1RN (intron 2, variable number tandem repeat) (Figure). De-tails of these polymorphisms and allele definition are listed in Table 2. The genomic DNA was prepared from peripheral blood by a Genomaker reagent kit (Blossom, Taichung). Polymerase chain reaction isolated the genotypes of all 3 IL-1–related genes. Restriction length fragment polymorphism for the 2 loci, IL1B promoter and IL1B exon, were studied. Primers and polymerase chain reaction conditions for the IL1B promoter, IL1B exon, and IL1RN polymorphisms are also listed in Table 2, according to the reports by Cantagrel et al20and Hang et al.26Polymerase chain reaction amplification was performed in a programmable ther-mal cycler GeneAmp PCR System 2400 (PerkinElmer, Welles-ley, Mass). Genotypes were scored by investigators blinded to clini-cal phenotype. The prevalence of these polymorphisms was compared between the CRS group and the control group. Table 1. Case and Control Demographics, Allergy Results,

and Clinical Information

Variable CRS (n = 88) Control (n = 103) P Value Age, mean ± SD, y 43.8 ± 17.1 38 ± 12.8 ⬎.05 Sex, M/F 57/31 59/44 ⬎.05 Phenotype, No. (%) With or without NPs CRS with NPs 61 (69) . . . . CRS without NPs 27 (31) . . . . Nonatopic CRS 51 (58) . . . .

Abbreviations: CRS, chronic rhinosinusitis; NPs, nasal polyps.

Chromosome 2 2q13-14 IL-1Ra Gene IL-1β Gene VNTR −511 +3953

Figure. Diagram showing locations of the single base pair polymorphisms in the 5⬘ flanking region of the interleukin (IL)-1␤ gene. Numbers refer to base pairs 5⬘ of the transcription start site. The polymorphism in the IL-1Ra gene is a variable number tandem repeat (VNTR) of an 86–base pair segment in intron 2.

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STATISTICAL ANALYSIS

The genotype frequencies distributions of these polymor-phisms in the control and CRS patient groups were compared by the␹2test. When the assumption of the␹2test was violated (ie, when 1 cell had an expected count of⬍1% or ⬎20% of the cells had an expected count of⬍5%), the Fisher exact test was used. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined for disease susceptibility of specific alleles in the polymorphism of IL-1Ra gene. Results were considered sta-tistically significantly when the probability of findings occur-ring by chance was less than 5% (P⬍.05). Performing power analysis and sample size estimation is an important aspect of experimental design; therefore, the power of the designed ex-periment was also calculated by SPSS for Windows, version 10.0 (SPSS Inc, Chicago, Ill). The result of the calculation was 89.8%, which indicates the sample size is not too low and the experi-ment will not lack the precision to provide reliable answers to the questions it is investigating.

RESULTS

The distribution of the IL1B promoter and IL1B exon poly-morphism and the corresponding genotype frequencies are given inTable 3. There was no significant differ-ence between the patients with CRS and the control sub-jects. InTable 4, the distribution of the IL1RN geno-type in the control group revealed 95 I/I allele homozygotes (92%), 6 I/II allele heterozygotes (6%), 1 II/II allele homozygote (1%), and 1 IV/IV allele homo-zygote (1%). The distribution of the IL1RN genotype in the CRS group showed 70 I/I allele homozygotes (80%), 15 I/II allele heterozygotes (17%), 1 II/II allele homozy-gote (1%), and 2 I/IV allele heterozyhomozy-gotes (2%). There were significant differences in the distribution of the IL-1Ra gene polymorphism between the patients with CRS and the control subjects (P⬍.05). To analyze a possible

polymorphism in linkage disequilibrium, only the num-ber of persons carrying I/I or I/II genotypes were counted, while persons carrying II/II, I/IV, or IV/IV genotypes were excluded because of their low number. The I/II geno-type occurred more frequently in the patients with CRS than in healthy controls, with an OR of 3.39 (95% CI, 1.25-9.18). An age-adjusted test for the I/I and I/II geno-types of IL1RN polymorphism indicated that age did not influence the result (OR, 2.87; 95% CI, 1.05-7.89). The results suggest that only the distribution of the IL-1Ra gene polymorphism was significantly different between the control group and the patients with CRS. There was no association between the other 2 polymorphisms of the IL-1␤ gene and CRS.

Table 2. Details of Polymorphisms and PCRs Used for Screening

Variable IL1B Promoter IL1B Exon IL1RN

Type of polymorphism Single base C→T Single base C→T 86-bp VNTR

Site of polymorphism Position −511 Exon 5 Intron 2

Allele definition C allele = cytosine at −511; T allele = thymine at −511

E1 allele = cytosine at⫹3953;

E2 allele = thymine at⫹3953 I allele = 4 repeats;II allele = 2 repeats; III allele = 5 repeats; IV allele = 3 repeats; V allele = 6 repeats PCR primers

Upstream 5⬘-TGGCATTGATC-TGGTTCATC-3⬘ 5⬘-GTTGTCATCAG-ACTTTGACC-3⬘ 5⬘-CTCAGCAA-CACTCCTAT-3⬘

Downstream 5⬘-GTTTAGGAATC-TGGACCAGA-3⬘ 5⬘-TTCAGTTCATA-TGGACCAGA-3⬘ 5⬘-TCCTGGTCT-GCAGGTAA-3⬘

PCR conditions

Denaturation 95°C, 30 s 95°C, 30 s 95°C, 30 s

Annealing 55°C, 30 s 55°C, 30 s 58°C, 30 s

Extension 72°C, 30 s 72°C, 30 s 72°C, 30 s

No. of cycles 30 30 35

Digestion Yes (Ava I) Yes (Tag I) No

PCR product size C allele = 190⫹ 114 bp; T allele = 304 bp E1 allele = 135⫹ 114 bp; E2 allele = 249 bp I allele = 410 bp; II allele = 240 bp; III allele = 500 bp; IV allele = 325 bp; V allele = 595 bp Abbreviations: bp, base pairs; PCR, polymerase chain reaction.

Table 3. Distribution of IL1B Promoter and IL1B Exon Polymorphism Between Control Subjects

and Patients With CRS*

Genotype Patients With CRS Control Subjects P Value IL1B promoter C/C 23 (26) 27 (27) .69† C/T 48 (55) 51 (50) T/T 17 (19) 25 (24) Total 88 (100) 103 (100) IL1B exon E1/E1 86 (98) 98 (95) .29‡ E1/E2 2 (2) 5 (5) E2/E2 0 0 Total 88 (100) 103 (100) Abbreviation: CRS, chronic rhinosinusitis.

*Data are given as number (percentage) of subjects unless otherwise specified. Percentages may not add to 100 because of rounding.

†␹2Test.

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We also studied the subgroups of patients with CRS of various etiologic factors. For patients with or without nasal polyps, the distributions of the IL1B promoter, IL1B exon, and IL1RN polymorphism were compared with con-trol subjects (Table 5). There were significant differ-ences only in the distribution of the IL-1Ra gene poly-morphism between the patients with CRS without nasal polyps and the control subjects (P⬍.05) (Table 5). This was mainly because of the increased number of I/II geno-types among patients with CRS without nasal polyps than among control subjects, with an OR of 4.75 (95% CI, 1.39-16.25); the OR was 4.26 for II allele frequency (95% CI, 1.31-13.82). Of CRS patients without allergy, the fre-quency distribution of IL-1Ra and IL-1␤ genotypes is listed Table 6, which indicated there was no significant dif-ference between the nonatopic patients with CRS and the control subjects.

COMMENT

Our results suggest that the frequency of II allele of the IL-1Ra gene polymorphism is significantly higher in Tai-wanese patients with CRS than in the control subjects. No significant association was identified in the distribu-tions of IL1B genotype with CRS subgroups, although IL-1␤ has been proposed to play a role in the develop-ment of nasal polyps.27,28In our control group, the alle-lic frequencies of the IL1B promoter were similar with those previously reported in other healthy controls.13,17 However, there was a relatively low incidence of the II allele of the IL1RN polymorphism and the E2 allele of the IL1B exon polymorphism in our control group. Popu-lation differences could be a contributing factor.

The IL-1Ra gene lies within the IL-1 gene cluster, on chromosome 2 (q14-q21), close to the IL-1␣ and IL-1␤ genes that mediate inflammation.29As observed in our study, III, IV, and V alleles are uncommon and account for less than 5%.13,17Because there are 3 potential protein-binding sites located within the repeated sequence, the number of repeats may influence gene transcription and protein production.30,31Because proinflammatory re-sponses elicited by IL-1␤ could be down-regulated by IL-1Ra, decreased production of IL-1Ra might be a sig-nificant predisposing factor to the chronicity of an

inflam-matory disease. Moreover, increased frequency of the II allele of this polymorphism has also been previously found to be associated with a variety of chronic inflam-matory diseases, such as systemic lupus erythema,15 in-flammatory bowel diseases,14,32and asthma.21,22

The association of sinusitis and asthma with histo-pathologic features, disease severity, and therapeutic out-come was recognized for a long time, and many studies indicated that the association reflects a systemic inflam-matory process of respiratory mucosa.33-35Mao et al22 con-ducted a genetic association study in a Japanese popu-lation to test whether variants of IL-1 relate to asthma. They found that the II allele of IL1RN is associated with nonatopic asthma. This allele is strongly associated with lower IL-1Ra levels, which may promote chronic inflam-matory reaction induced by IL-1␤ in nonatopic asthma. Chronic rhinosinusitis has diverse etiologic factors. It could be divided into CRS with or without nasal pol-yposis because these 2 have been shown to have differ-Table 4. Distribution of IL1RN Polymorphism Between

Control Subjects and Patients With CRS*

IL1RN Genotype Patients With CRS Control Subjects P Value I/I 70 (80) 95 (92) .01† I/II 15 (17) 6 (6) II/II 1 (1) 1 (1) I/IV 2 (2) 0 IV/IV 0 1 (1) Total 88 (100) 103 (100)

Abbreviation: CRS, chronic rhinosinusitis.

*Data are given as number (percentage) of subjects unless otherwise specified.

†Fisher exact test.

Table 5. Distribution of IL1B and IL1RN Polymorphisms Between Control Subjects and Patients With CRS With or Without Nasal Polyps*

Genotype Patients With CRS Control Subjects P Value IL1B promoter C/C 16 (26) 27 (27) .77† C/T 33 (54) 51 (50) T/T 12 (20) 25 (24) Total 61 (100) 103 (100) IL1B exon E1/E1 59 (97) 98 (95) .48‡ E1/E2 2 (3) 5 (5) E2/E2 0 0 Total 61 (100) 103 (100) IL1RN I/I 50 (82) 95 (92) .09‡ I/II 9 (15) 6 (6) II/II 1 (2) 1 (1) I/IV 1 (2) 0 IV/IV 0 1 (1) Total 61 (100) 103 (100) IL1B promoter C/C 7 (26) 27 (27) .79† C/T 15 (56) 51 (50) T/T 5 (19) 25 (24) Total 27 (100) 103 (100) IL1B exon E1/E1 27 (100) 98 (95) .31‡ E1/E2 0 5 (5) E2/E2 0 0 Total 27 (100) 103 (100) IL1RN I/I 20 (74) 95 (92) .02‡ I/II 6 (22) 6 (6) II/II 0 1 (1) I/IV 1 (4) 0 IV/IV 0 1 (1) Total 27 (100) 103 (100) Abbreviation: CRS, chronic rhinosinusitis.

*Data are given as number (percentage) of subjects unless otherwise specified. Percentages may not add to 100 because of rounding.

†␹2Test.

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ent types of inflammatory cells and different levels of in-flammatory cytokines.5In this regard, we examined the distributions of the 3 polymorphisms in the 2 sub-groups of patients with CRS compared with control subjects. There were significant differences in the distri-bution of the IL1RN polymorphism between the pa-tients with CRS without nasal polyps and the control sub-jects; there were no significant differences between the patients with CRS with nasal polyps and the control sub-jects. The different results from the 2 subgroups of pa-tients with CRS could also provide a genetic basis, to a certain extent, for such a classification of CRS.

There are numerous factors contributing to the patho-genesis and chronicity of CRS, including genetics, ana-tomic anomalies, bacteria, and fungus. Allergic rhinitis, cystic fibrosis, mucociliary disorders, and gastroesopha-geal reflux are also thought to affect the presentation of the disease.36-39Nevertheless, almost of all these complexi-ties could be simplified by stringent screening and by clas-sifying patients during history taking, imaging, physical and laboratory examinations, operative finding, and patho-logical review. Because single nucleotide substitutions in several genes have been reported to be associated with al-lergic diseases,40,41we subgrouped patients with CRS and focused on patients with CRS without allergy (nonatopic CRS) to test if variants of IL1RN related to CRS. How-ever, no significant difference was seen in the frequencies of IL-1Ra and IL-1␤ genotypes compared with the con-trol subjects.

Chronic rhinosinusitis is a common chronic illness. It is likely that inflammation and genetics are both es-sential mechanisms in the pathogenesis of CRS. A better understanding of the cause and pathophysiologic mecha-nisms of CRS at the molecular level may provide new guides for diagnosis and therapeutic strategies.10Both IL-1␤ and IL-1Ra are cytokines that play key roles in im-mune responses, inflammation, and fibrosis. Single nucleotide polymorphisms have important implica-tions in human genetic research, and an understanding of the polymorphisms associated with CRS is expected to increase the comprehension of the course of the dis-ease. While a genetic association between a variant of IL-1␣ with nasal polyps in patients with asthma has been identified,21to our knowledge, no intensive study on poly-morphisms of IL1B and IL1RN in relation to CRS was re-ported to date. We found that the II allele of IL1RN oc-curred more frequently in patients with CRS than in healthy patients. This allele might be associated with lower IL-1Ra levels, which may promote chronic inflamma-tory reaction induced by IL-1␤ in CRS. However, the prevalence of the one polymorphism shown to be statis-tically associated with the chronic sinusitis phenotype was low. Thus, while 17% of patients with CRS ex-pressed a particular set of alleles for the IL-1Ra gene (and this was statistically significant), this level of associa-tion implies that if such a genotype plays a role in the pathogenesis of the disease, it could be operating in the minority of cases. Further studies should be conducted to clarify this polymorphism with disease severity or with in vitro gene expression, such as serum levels of IL-1Ra. In conclusion, our data demonstrate an increased prevalence of I/II heterozygotes of the IL-1Ra gene

poly-morphism in a Taiwanese population of patients with CRS compared with control subjects. This implies that this polymorphism, or a variant in linkage disequilibrium with it, may be involved in determining the genetic suscepti-bility and pathogenesis of CRS. However, the underly-ing mechanism of the association needs to be clarified in the future.

Submitted for Publication: November 22, 2004; final

re-vision received August 9, 2005; accepted August 18, 2005.

Correspondence: Fuu-Jen Tsai, MD, PhD, Department

of Medical Genetics and Pediatrics, China Medical Uni-versity Hospital, No. 2 Yuh-Der Rd, Taichung 404, Tai-wan (keiko56@ms25.hinet.net).

Author Contributions: Dr Cheng had full access to all

the data in the study and takes responsibility for the in-tegrity of the data and the accuracy of the data analysis.

Financial Disclosure: None.

Acknowledgment: We thank Yu-Hsiao Wu, MS, of the

Department of Medical Genetics and Pediatrics, China Medical University Hospital, for the acquisition of data.

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Table 6. Distribution of IL1B and IL1RN Polymorphisms Between Control Subjects and Patients With

Nonatopic Chronic Rhinosinusitis*

Genotype CRS Without Allergy Control Subjects P Value IL1B promoter C/C 15 (29) 27 (27) .64† C/T 27 (53) 51 (50) T/T 9 (18) 25 (24) Total 51 (100) 103 (100) IL1B exon E1/E1 50 (98) 98 (95) .35‡ E1/E2 1 (2) 5 (5) E2/E2 0 0 Total 51 (100) 103 (100) IL1RN I/I 44 (86) 95 (92) .19‡ I/II 5 (10) 6 (6) II/II 0 1 (1) I/IV 2 (4) 0 IV/IV 0 1 (1) Total 51 (100) 103 (100)

*Data are given as number (percentage) of subjects unless otherwise specified. Percentages may not add to 100 because of rounding.

†␹2test.

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數據

Table 1. Case and Control Demographics, Allergy Results, and Clinical Information
Table 2. Details of Polymorphisms and PCRs Used for Screening
Table 5. Distribution of IL1B and IL1RN Polymorphisms Between Control Subjects and Patients With CRS With or Without Nasal Polyps*
Table 6. Distribution of IL1B and IL1RN Polymorphisms Between Control Subjects and Patients With

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