Genetic and biochemical markers of obstructive lung disease in the general population.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
INTRODUCTION: New markers of early disease activity and prognosis are needed in asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: To identify new markers of asthma and COPD to implement in clinical practice, we genotyped for common genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), alpha(1)-antitrypsin, and mannose-binding lectin (MBL) genes, and measured baseline fibrinogen and C-reactive protein (CRP) concentrations in up to 9245 adults randomly selected from the Danish general population. MATERIALS AND METHODS: Information on diagnoses of asthma and COPD was collected from two Danish National Registers covering all hospital discharges and deaths in the country. This data was correlated with genotyping results to determine risk of obstructive lung disease according to the genetic and biochemical markers studied. RESULTS: The genetic marker, F508del, in the cystic fibrosis gene was associated with increased asthma risk, but aggregating this data in a meta-analysis with results from previous reports, the risk of asthma was only marginally elevated [summary odds ratio (95%CI): 1.3 (1.1-1.6)]. The F508del marker was not associated with COPD [odds ratio: 0.9 (0.4-1.6)]. Our data also suggested a significant role of smoking on fertility in cystic fibrosis/F508del heterozygotes. The risk of COPD was marginally elevated for the genetic markers, MS and MZ, in the alpha(1)-antitrypsin gene [summary odds ratio: MS, 1.2 (1.0-1.4) and MZ, 2.3 (1.6-3.4)], whereas the SZ marker was an important risk factor of COPD [summary odds ratio: 3.3 (1.2-8.6)]. The ZZ genotype is already in clinical use as a genetic marker for early-onset COPD. Our data also suggested ZZ and MZ are associated with reduced blood pressure and MZ with reduced risk of ischemic cardiovascular disease. Genetic deficiency of MBL was not a major risk factor for asthma [relative risk: 1.1 (0.8-1.7)] or COPD [1.4 (0.97-2.0)]. We found increased risk of cardiovascular disease with MBL deficiency, but this result could not be confirmed in a matched case-control study using cases with ischemic cardiovascular disease from Copenhagen University Hospital, Denmark. Elevated serum fibrinogen and CRP levels were biochemical markers of future COPD. In the future after further validation, it is possible that these markers, particularly CRP, can be used to categorize individuals with low, medium, or high risk of COPD, and thus point out patients in need of intensified prevention and treatment for COPD. The association between COPD and elevated fibrinogen and CRP levels suggests that either factor or upstream factors regulating fibrinogen and CRP expression are important players in the pathogenesis of COPD. CONCLUSION: We have set-up an analysis for diagnosing the SZ and ZZ genotypes at the Department of Clinical Biochemistry at Herlev University Hospital, together with measurement of plasma alpha(1)-antitrypsin levels. This will help clinicians to detect alpha(1)-antitrypsin-deficient individuals with a high risk for COPD, and opens up for early smoking prevention counseling and potential therapy for individuals identified with alpha(1)-antitrypsin deficiency. The F508del marker and genetic variants in the MBL-2 gene cannot at present be used as markers for obstructive lung disease in the Danish general population. To determine whether fibrinogen or CRP is causally related to COPD, we are currently investigating whether genetically reduced levels of fibrinogen and CRP are associated with reduced risk of future COPD.
|Tidsskrift||The Clinical Respiratory Journal|
|Status||Udgivet - 1 jan. 2009|