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In order to determine the possible role of the cystic fibrosis transmembrane regulator (CFTR) gene in pulmonary diseases not due to cystic fibrosis, a complete screening of the CFTR gene was performed in 120 Italian patients with disseminated bronchiectasis of unknown cause (DBE), chronic bronchitis (CB), pulmonary emphysema (E), lung cancer (LC), sarcoidosis (S) and other forms of pulmonary disease. The 27 exons of the CFTR gene and their intronic flanking regions were analyzed by denaturing gradient gel electrophoresis and automatic sequencing. Mutations were detected in 11/23 DBE (P = 0.009), 7/25 E, 5/27 CB, 5/26 LC, 5/8 S (P = 0.013), 1/4 tuberculosis, and 1/5 pneumonia patients, and in 5/33 controls. Moreover, the IVS8-5T allele was detected in 6/25 E patients (P = 0.038). Four new mutations were identified: D651N, 2377C/T, E826K, and P1072L. These results confirm the involvement of the CFTR gene in disseminated bronchiectasis of unknown origin, and suggest a possible role for CFTR gene mutations in sarcoidosis, and for the 5T allele in pulmonary emphysema.

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Genetic factors are believed to play a role in the individual susceptibility to chronic obstructive pulmonary disease (COPD). Tumour necrosis factor (TNF) family genes have been widely investigated but inconsistent results may lie either in the genetic heterogeneity of populations or in the poor phenotype definition. A genetic study was performed using a narrower phenotype of COPD.The authors studied 86 healthy smokers and 63 COPD subjects who were enrolled based on irreversible airflow obstruction (forced expiratory volume in one second/forced vital capacity v70% predicted) and a diffusing capacity for carbon monoxide v50% predicted (moderate-to-severe COPD associated with pulmonary emphysema). The following polymorphisms were investigated: TNF-308, the biallelic polymorphism located in the first intron of the lymphotoxin-a gene, and exon 1 and exon 6 of the TNF receptor 1 and 2 genes, respectively.No significant deviations were found concerning the four polymorphisms studied between the two populations.The authors confirm that the tumour necrosis factor family genes, at least for the polymorphisms investigated, are not major genetic risk factors for chronic obstructive pulmonary disease in Caucasians, either defined in terms of emphysema (this study) or airflow obstruction (previous studies). Nevertheless, the authors would like to emphasise the importance of narrowing the phenotype in the search for genetic risk factors in chronic obstructive pulmonary disease. Eur Respir J 2003; 21: 444-449.

Obstructive pulmonary disease is a multifactorial condition deriving from the interaction of environmental and genetic factors. From biochemical knowledge of the basis of the disease, alpha 1-antitrypsin and alpha 1-antichymotrypsin are considered two likely candidate genes. We therefore designed an association study comprising 232 unrelated Italian individuals divided as follows: 89 individuals with obstructive lung disease (66 with COPD and 23 with disseminated bronchiectasis) and 143 controls (45 patients with non-obstructive lung disease and 98 healthy individuals). We screened for Taq I (G1237A) polymorphism of the alpha 1-antitrypsin gene as well as the rare variants Bonn-1 (Pro229Ala), Bochum-1 (Leu55Pro), Isehara-1 (Met389Val) and Isehara-2 (1258delAA), and the common signal peptide polymorphism Thr-15Ala of the alpha 1-antichymotrypsin gene. The frequencies of Taq I G1237A alleles were 11.7 and 10.8% in obstructed patients and controls, respectively (P = 0.43), while those of signal peptide Thr-15Ala alleles were 51.6 and 50.3% in obstructed patients and controls, respectively (P = 0.42). We conclude that alpha 1-antitrypsin Taq I polymorphism and alpha 1-antichymotrypsin Thr-15Ala mutation are not major genetic risk factors for the development of obstructive lung disease in Italian patients. The alpha 1-antichymotrypsin rare variants were not detected: our results do not exclude the possibility that other alpha 1-antichymotrypsin gene mutations might be present in Italian obstructed patients but, if so, these genetic defects must be rare.

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