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Neutrophil and monocyte activation contribute to the pathology of chronic obstructive pulmonary disease (COPD). We hypothesised that a known polymorphism in a key lipopolysaccharide (LPS) response gene might reduce the severity of COPD through a decreased cellular response to activators inhaled in cigarette smoke. TLR4 is the protein enabling signalling to bacterial LPS and perhaps to endogenous mediators of inflammation, and is an important regulator of leucocyte function.1 Functional polymorphisms in TLR4 have been described and their roles investigated in a number of diseases. Most studies have focused on the Asp299Gly polymorphism, with the rare allele (Gly299) causing LPS hyporesponsiveness.2 In a study of more than 800 subjects the presence of the TLR4 polymorphism was associated with a reduced risk of atherosclerosis.3 Smaller studies have potentially associated TLR4 polymorphisms with increased risk of sepsis4 but, in a large study of patients with meningococcal disease, Asp299Gly was not associated with either altered risks of, or outcomes following, meningitis;5 although a recent study has suggested that rarer polymorphisms in TLR4 may be important in this disease.6
We screened a population of smokers recruited on the basis of age >40 and a smoking history of at least 10 pack years for the presence of the TLR4 polymorphism by established techniques in our group.5 Data were available on 289 subjects, of which 260 were Asp299 homozygotes and 29 heterozygotes. No Gly299 homozygotes were detected (these data correlate closely with the known frequency of the polymorphism in our region5). The presence of the TLR4 polymorphism did not have any significant impact on lung function (measured as forced expiratory volume in 1 second (FEV1) before and after bronchodilator challenge).
These data do not exclude the possibility that the well characterised and relatively common Asp299Gly TLR4 polymorphism might have a small effect on the severity of COPD. To examine fully the role of this TLR4 polymorphism, large populations (>1000) will be required to give adequate power to exclude small effects on FEV1 or reversibility. However, the current study shows that this polymorphism is unlikely to have a major impact on the severity of COPD at the population level.