The CFTR M470V Gene Variant as a Potential Modifier of COPD Severity: Study of Serbian Population Marija Stankovic, 1 Aleksandra Nikolic, 1 Aleksandra Divac, 1 Andrija Tomovic, 2 Natasa Petrovic-Stanojevic, 3 Marina Andjelic, 3 Vesna Dopudja-Pantic, 3 Mirjana Surlan, 3 Ivan Vujicic, 3 Dimitrije Ponomarev, 3 Marija Mitic-Milikic, 4 Jelena Kusic, 1 and Dragica Radojkovic 1 Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by genetic and environmental factors. Cystic fibrosis transmembrane conductance regulator (CFTR) protein is an important component of the lung tissue homeostasis, involved in the regulation of the rate of mucociliary clearance. As it is known that certain CFTR variants have consequences on the function of CFTR protein, the aim of this study was to examine the possible role of F508del, M470V, Tn locus, and R75Q variants in COPD development and modulation. Total number of 86 COPD patients and 102 control subjects were included in the study. Possible association between COPD susceptibility, severity, and onset of the disease and allele or genotype of four analyzed CFTR variants was examined. No associations were detected between COPD development, onset of the disease and tested CFTR alleles and genotypes. However, VV470 genotype was associated with mild=moderate COPD stages in comparison to severe=very severe ones (OR ¼ 0.29, 95%CI ¼ 0.11–0.80, p ¼ 0.016). Our study showed that patients with VV470 genotype had a 3.4-fold decreased risk for the appearance of severe=very severe COPD symptoms, and the obtained results indicate that this genotype may have a protective role. These results also suggest the importance of studying CFTR gene as a modifier of this disease. Introduction C hronic obstructive pulmonary disease (COPD) is characterized by the progressive development of airflow limitation that is not fully reversible. It encompasses chronic bronchitis with obstruction and inflammation of small air- ways and emphysema with destruction of lung parenchyma and loss of lung elasticity (Barnes, 2000). Smoking is re- garded as the most important causal factor, suggesting the importance of environmental factors. However, only a min- ority of smokers develop symptomatic COPD, which in- dicates that a difference in susceptibility to tobacco smoke injury might be related to genetic factors. It is likely that multiple genetic factors interact with each other and with environmental factors resulting in pathophysiological het- erogeneity observed in COPD (Walter et al., 2000). The genes that are involved in processes, such as extracellular matrix remodeling, antiproteolysis, metabolism of toxic substances from cigarette smoke, inflammation, and mucociliary clear- ance, may be responsible for COPD development ( Joos et al., 2002; Wood and Stockley, 2006). Different genetic variants, in the same gene or in different genes, may alter or modulate processes that could lead to initiation and progression of COPD pathogenesis. The only established genetic risk factor for COPD, so far, is homozygosity for Z allele of the a-1-antitrypsin gene, but the carriers of this genotype account for a small proportion of all patients ( Joos et al., 2002). Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are considered to be involved in COPD pathogenesis, but there is still no strong evidence that they alone could cause the disease (Tzetis et al., 2001). Mutations and polymorphisms in the CFTR gene have been found in several lung disorders (Noone and Knowles, 2001). Although the normal expression of the CFTR in the lung is lower compared to tissues such as the intestine and pan- creas, its function in the lung is of major importance. In ad- dition to functioning as a chloride channel, CFTR has also been implicated in the regulation of the rate of mucociliary clear- ance (Jiang and Engelhardt, 1998). Defective CFTR function 1 Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia. 2 Friedrich Miescher Institute for Biomedical Research, Part of the Novartis Research Foundation, Basel, Switzerland. 3 Zvezdara University Medical Center, Belgrade, Serbia. 4 Institute for Tuberculosis and Lung Disease, University Clinical Center of Serbia, Belgrade, Serbia. GENETIC TESTING Volume 12, Number 3, 2008 ª Mary Ann Liebert, Inc. Pp. 357–362 DOI: 10.1089=gte.2007.0069 357