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Tohoku University School of Medicine, Sendai, 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{at}geriat.med.tohoku.ac.jp
To the Editor:
We read with interest the article by Hegab et al.1 Although interleukin (IL)-1ß is also thought to be one of the important cytokines in COPD, Joos et al2 failed to show the relationship between functional single nucleotide polymorphisms at the IL-1ß promotor gene at position –511. However, since their reports were published, there was an explosion of reports revealing the association between IL-1ß –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-1ß polymorphisms at positions –31 and –511, polymerase chain reaction and restriction enzyme fragment length polymorphisms were performed on blood samples.23 Table 1 shows the characteristics of 85 COPD patients and 68 healthy subjects and the distribution of IL-1ß –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-1ß –31 and –511 loci had linkage disequilibrium, there were no differences on the C allele –31 and genotyped frequency of IL-1ß between the COPD patients and the control subjects.
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* University of Tsukuba Ibaraki, Japan
Correspondence to: Kiyohisa Sekizawa, MD, Department of Pulmonary Medicine, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences and University Hospital, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan; e-mail: kiyo-se{at}md.tsukuba.ac.jp
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, IL1ß 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 IL1ß 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 IL1ß gene. El-Omar and colleagues2 have demonstrated the possibility that the IL1ß –31 T/C polymorphism, but not the –511 C/T polymorphism, has an influence on the transcriptional activity of the IL1ß gene. The IL1ß –511 C/T polymorphism was shown to be in almost complete linkage disequilibrium (LD) with IL1ß –31 T/C both in white subjects2 and Japanese subjects.3 Therefore, the effect of the IL1ß –511 C/T polymorphism may be due to the LD with IL1ß –31 T/C polymorphism. However, Asada and colleagues detected less than complete LD between these two polymorphisms, and only the IL1ß –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 colleagues4 have demonstrated that the haplotypes consisting of IL1ß –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 IL1ß/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 IL1ß. In addition, the IL1ß +3954 C/T polymorphism is also related to IL1ß production.7 Both of the IL1ß 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
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