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Communications to the Editor |

Interleukin-1β Gene Polymorphisms Associated With COPD FREE TO VIEW

Masanori Asada, MD; Mutsuo Yamaya, MD; Satoru Ebihara, MD; Hiroyasu Yasuda, MD; Naoki Tomita, MD; Hiroshi Kubo, MD; Hidetada Sasaki, MD
Author and Funding Information

Affiliations: Tohoku University School of Medicine, Sendai, Japan,  *University of Tsukuba Ibaraki, Japan

Correspondence to: Masanori Asada, MD, Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan; e-mail: asada@geriat.med.tohoku.ac.jp



Chest. 2005;128(2):1072-1073. doi:10.1378/chest.128.2.1072
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To the Editor:

We read with interest the article by Hegab et al.1Although interleukin (IL)-1β is also thought to be one of the important cytokines in COPD, Joos et al2failed to show the relationship between functional single nucleotide polymorphisms at the IL-1β promotor gene at position −511. However, since their reports were published, there was an explosion of reports revealing the association between IL-1β −511 polymorphisms and a variety of diseases ranging from psychological3 to dental disease.4 Therefore, completely healthy elderly people were recruited from a large health survey in the Sendai area.

To elucidate the genotype of IL-1β polymorphisms at positions −31 and −511, polymerase chain reaction and restriction enzyme fragment length polymorphisms were performed on blood samples.23Table 1 shows the characteristics of 85 COPD patients and 68 healthy subjects and the distribution of IL-1β −511 and −31 genotypes in these two groups. The T allele at −511 SNP (p = 0.02) was overrepresented in the healthy control subjects. The homozygote subjects were particularly at lower risk for COPD, with an odds ratio of 0.43 for −511 C/C and T/C. Although IL-1β −31 and −511 loci had linkage disequilibrium, there were no differences on the C allele −31 and genotyped frequency of IL-1β between the COPD patients and the control subjects.

Different from the report Joos et al,2we showed a significant association between only the T allele at −511 SNP and susceptibility to COPD. First, because both the COPD patients and the control subjects were elderly, we suspect that the IL-1β −511 loci strongly affects susceptibility to COPD with chronic inflammation for a long time. Second, since there is much evidence linking IL-1β −511 polymorphisms and other diseases,5 healthy elderly smokers who have not had these diseases may have the T allele at −511 SNP. Since there were no differences in the distribution of IL-1β polymorphisms at position −31 between the COPD patients and the control subjects, we believe that our sample size was not large enough to detect small differences between the two groups. Polymorphisms of IL-1β at the position −511 are associated with susceptibility to COPD.

Table Graphic Jump Location
Table 1. IL-1β Genotypes in Healthy Control Subjects and COPD Patients*
* 

Data are presented as mean ± SEM or No. (%) unless otherwise indicated.

Hegab, EA, Sakamoto, T, Saitoh, W, et al (2004) Polymorphisms of IL-4, IL-13, ADRB2 genes in COPD.Chest126,1832-1839. [CrossRef] [PubMed]
 
Joos, L, McIntyre, L, Ruan, J, et al Association of IL-1β and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.Thorax2001;56,863-866. [CrossRef] [PubMed]
 
Craig, D, Hart, DJ, McCool, K, et al The interleukin 1β gene promoter polymorphism (-511) acts as a risk factor for psychosis in Alzheimer‘s dementia.Ann Neurol2004;56,121-124. [CrossRef] [PubMed]
 
Kinane, DF, Hart, TC Genes and gene polymorphisms associated with periodontal disease.Crit Rev Oral Biol Med2003;14,430-449. [CrossRef] [PubMed]
 
Zienolddiny, S, Ryberg, D, Maggini, V, et al Polymorphisms of the interleukin-1β gene are associated with increased risk of non-small cell lung cancer.Int J Cancer2004;109,353-356. [CrossRef] [PubMed]
 
To the Editor:

We thank Dr. Asada and colleagues for their comments on our article in CHEST (December 2004),1 and we appreciate the opportunity to respond. COPD is characterized by chronic inflammation in the airway and the parenchyma. Inflammatory cells such as macrophages, neutrophils, and CD8+ T lymphocytes release a variety of mediators, proteases, and oxidants. These inflammatory events induce mucus hypersecretion, bronchial smooth muscle hypertrophy, airway hyperresponsiveness, remodeling and narrowing of the small airways, and parenchymal destruction, all of which result in airflow limitation. Based on this pathogenesis, we conducted a case-control association analysis for some polymorphisms of the interleukin (IL)4, IL13, and ADRB2 genes. Similarly, IL1β is a good candidate gene for COPD association analysis.

Asada and colleagues conducted a case-control study to examine the association of two polymorphisms, −511 C/T and −31 T/C, of the IL1β gene with the development of COPD. Although it is difficult to understand their results without knowledge of the details of the recruitment criteria of the COPD patients, we have some general comments on their study. The −31 T/C polymorphism is situated on a TATA box in the promoter region of the IL1β gene. El-Omar and colleagues2 have demonstrated the possibility that the IL1β −31 T/C polymorphism, but not the −511 C/T polymorphism, has an influence on the transcriptional activity of the IL1β gene. The IL1β −511 C/T polymorphism was shown to be in almost complete linkage disequilibrium (LD) with IL1β −31 T/C both in white subjects,2and Japanese subjects.3 Therefore, the effect of the IL1β −511 C/T polymorphism may be due to the LD with IL1β −31 T/C polymorphism. However, Asada and colleagues detected less than complete LD between these two polymorphisms, and only the IL1β −511 C/T polymorphism was associated with COPD. Whether this was due to the relatively small sample size or to some bias in the recruitment of the subjects remains to be elucidated.

Joos and colleagues4have demonstrated that the haplotypes consisting of IL1β −511 C/T polymorphism and variable numbers of tandem repeat in intron 2 of the IL1 receptor antagonist (IL1RN) gene play a role in the rate of decline in FEV1 in smokers. It is recognized that IL1β/IL1RN ratio is critical in determining the severity of inflammatory reactions.5 The two repeat alleles of the IL1RN variable numbers of tandem repeat polymorphism has been reported6 to be associated with increased production of IL1β. In addition, the IL1β +3954 C/T polymorphism is also related to IL1β production.7 Both of the IL1β and IL1RN genes are located on chromosome 2q14. Therefore, we think that it would have been better for Asada and colleagues to have studied more polymorphisms of the IL1 gene complex both individually and as haplotypes, since haplotype analysis may demonstrate genetic influences that are not detected by the analysis of single polymorphisms.

References
Hegab, AE, Sakamoto, T, Saitoh, W, et al Polymorphisms of IL4, IL13, and ADRB2 genes in COPD.Chest2004;126,1832-1839. [CrossRef] [PubMed]
 
El-Omar, EM, Carrington, M, Chow, WH, et al Interleukin-1 polymorphisms associated with increased risk of gastric cancer.Nature2000;404,398-402. [CrossRef] [PubMed]
 
Wang, Y, Kato, N, Hoshida, Y, et al Interleukin-1β gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.Hepatology2003;37,65-71. [CrossRef] [PubMed]
 
Joos, L, McIntyre, L, Ruan, J, et al Association of IL-1β and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.Thorax2001;56,863-866. [CrossRef] [PubMed]
 
Dinarello, CA Biologic basis for interleukin-1 in disease.Blood1996;87,2095-2147. [PubMed]
 
Santtila, S, Savinainen, K, Hurme, M Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1β productionin vitro.Scand J Immunol1998;47,195-198. [CrossRef] [PubMed]
 
Pociot, F, Molvig, J, Wogensen, L, et al A TaqI polymorphism in the human interleukin-1 β (IL-1 β) gene correlates with IL-1 beta secretionin vitro.Eur J Clin Invest1992;22,396-402. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. IL-1β Genotypes in Healthy Control Subjects and COPD Patients*
* 

Data are presented as mean ± SEM or No. (%) unless otherwise indicated.

References

Hegab, EA, Sakamoto, T, Saitoh, W, et al (2004) Polymorphisms of IL-4, IL-13, ADRB2 genes in COPD.Chest126,1832-1839. [CrossRef] [PubMed]
 
Joos, L, McIntyre, L, Ruan, J, et al Association of IL-1β and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.Thorax2001;56,863-866. [CrossRef] [PubMed]
 
Craig, D, Hart, DJ, McCool, K, et al The interleukin 1β gene promoter polymorphism (-511) acts as a risk factor for psychosis in Alzheimer‘s dementia.Ann Neurol2004;56,121-124. [CrossRef] [PubMed]
 
Kinane, DF, Hart, TC Genes and gene polymorphisms associated with periodontal disease.Crit Rev Oral Biol Med2003;14,430-449. [CrossRef] [PubMed]
 
Zienolddiny, S, Ryberg, D, Maggini, V, et al Polymorphisms of the interleukin-1β gene are associated with increased risk of non-small cell lung cancer.Int J Cancer2004;109,353-356. [CrossRef] [PubMed]
 
Hegab, AE, Sakamoto, T, Saitoh, W, et al Polymorphisms of IL4, IL13, and ADRB2 genes in COPD.Chest2004;126,1832-1839. [CrossRef] [PubMed]
 
El-Omar, EM, Carrington, M, Chow, WH, et al Interleukin-1 polymorphisms associated with increased risk of gastric cancer.Nature2000;404,398-402. [CrossRef] [PubMed]
 
Wang, Y, Kato, N, Hoshida, Y, et al Interleukin-1β gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.Hepatology2003;37,65-71. [CrossRef] [PubMed]
 
Joos, L, McIntyre, L, Ruan, J, et al Association of IL-1β and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.Thorax2001;56,863-866. [CrossRef] [PubMed]
 
Dinarello, CA Biologic basis for interleukin-1 in disease.Blood1996;87,2095-2147. [PubMed]
 
Santtila, S, Savinainen, K, Hurme, M Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1β productionin vitro.Scand J Immunol1998;47,195-198. [CrossRef] [PubMed]
 
Pociot, F, Molvig, J, Wogensen, L, et al A TaqI polymorphism in the human interleukin-1 β (IL-1 β) gene correlates with IL-1 beta secretionin vitro.Eur J Clin Invest1992;22,396-402. [CrossRef] [PubMed]
 
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