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We read with interest the paper by Joos et al1 on the association of IL-1 gene haplotypes with decline in lung function in smokers and share their view on a possible role of IL-1 genetics in inflammatory respiratory diseases. We have analysed the same polymorphism by the same methods in adult incident non-smoking asthmatic patients and non-smoking controls. Our results indicate that the association of IL-1 genetics with rate of decline in lung function is not limited to smokers.
New adult asthma cases and controls were selected from a cohort of the Mini-Finland Health Survey (MFHS) and later re-evaluated. A more detailed description of the methods used in MFHS has been published elsewhere.2 The accuracy of the method of asthma case ascertainment has also recently been described.3 IL-1 haplotypes were found to be significantly associated with the rate of decline of lung function in non-smoking incident cases of asthma (new asthma during follow up) but not in controls (table 1). Of the individual haplotypes, Joos et al found that IL1RN A1/IL1B –511T was associated with a rapid decline of lung function in smokers and IL1RN A2/IL1B –511T with a slow decline. In our control group the observed differences were not significant. Surprisingly, in the asthma group the haplotypes had the opposite effects from those in smokers: IL1RN A1/IL1B –511T was associated with a slower decline in lung function and IL1RN A2/IL1B –511T with a more rapid decline. IL1RN A2/IL1B –511T has previously been found to be associated with many inflammatory diseases.4 The function of these haplotypes would therefore appear to be disease specific.
Karajalainen and colleagues present interesting data on the relationship of IL-1β and IL-1 receptor antagonist haplotypes and the rate of decline of lung function in incident asthmatic subjects in a Finnish cohort. We reported that the ILIRN A1/IL1B –511T haplotype was associated with a more rapid decline in lung function in smokers in the Lung Health Study; in contrast, they found that this same haplotype was associated with a slower rate of decline in lung function in patients with asthma. The authors suggest that this apparent contradiction may be because the function of these haplotypes is disease specific. We agree that a different effect of the same haplotype could occur because of fundamental differences in the pathophysiological processes which cause airflow obstruction in asthma and chronic obstructive pulmonary disease (COPD). In asthma, CD4+ Th2 cells underlie persistent eosinophilic inflammation and remodelling in medium sized and larger airways. In COPD, neutrophils and CD8+ cells appear to play an important role in the airflow limitation by causing proteolytic destruction of peripheral lung parenchyma and fibrous scarring of the small membranous and respiratory bronchioles. Although inflammation appears to be central to both processes, the roles of IL-1β and of IL-1 receptor antagonist in these conditions is unknown and it is possible that the polymorphisms that are responsible for this haplotype could have opposite effects.
Alternatively, these apparently contradictory results could be due to different genetic histories of the two study groups. Our study group was taken from the white population in the United States whereas Karjalainen et al studied Finnish individuals. It may be that the polymorphisms which are typed to establish these haplotypes do not, by themselves, change the function or level of expression of the IL proteins but are in linkage disequilibrium with a causal polymorphism(s). In this case, the IL1 allelic associations could be different in different populations. The bottleneck in the genetic history of the Finnish people could have established a founder effect and resulted in the function altering allele being found on a different genetic background from that in the white population of the United States.
Whatever the correct explanation, these results support the growing evidence that genetic variation at the IL-1 locus is important in modulating the severity and/or functional consequences of a number of inflammatory conditions.
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