Research article

Folliculin mutations are not associated with severe COPD

Michael H Cho^1,2 , Barbara J Klanderman¹ , Augusto A Litonjua^1,2 , David Sparrow³ , Edwin K Silverman^1,2 and Benjamin A Raby^1,2

¹Channing Laboratory, Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School, Boston, MA, USA

²Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School, Boston, MA, USA

³Veterans Affairs Boston Healthcare System and Boston University Schools of Public Health and Medicine, Boston, MA, USA

author email corresponding author email

BMC Medical Genetics 2008, 9:120doi:10.1186/1471-2350-9-120

Published:	30 December 2008

Abstract

Background

Rare loss-of-function folliculin (FLCN) mutations are the genetic cause of Birt-Hogg-Dubé syndrome, a monogenic disorder characterized by spontaneous pneumothorax, fibrofolliculomas, and kidney tumors. Loss-of-function folliculin mutations have also been described in pedigrees with familial spontaneous pneumothorax. Because the majority of patients with folliculin mutations have radiographic evidence of pulmonary cysts, folliculin has been hypothesized to contribute to the development of emphysema.

To determine whether folliculin sequence variants are risk factors for severe COPD, we genotyped seven previously reported Birt-Hogg-Dubé or familial spontaneous pneumothorax associated folliculin mutations in 152 severe COPD probands participating in the Boston Early-Onset COPD Study. We performed bidirectional resequencing of all 14 folliculin exons in a subset of 41 probands and subsequently genotyped four identified variants in an independent sample of345 COPD subjects from the National Emphysema Treatment Trial (cases) and 420 male smokers with normal lung function from the Normative Aging Study (controls).

Results

None of the seven previously reported Birt-Hogg-Dubé or familial spontaneous pneumothorax mutations were observed in the 152 severe, early-onset COPD probands. Exon resequencing identified 31 variants, including two non-synonymous polymorphisms and two common non-coding polymorphisms. No significant association was observed for any of these four variants with presence of COPD or emphysema-related phenotypes.

Conclusion

Genetic variation in folliculin does not appear to be a major risk factor for severe COPD. These data suggest that familial spontaneous pneumothorax and COPD have distinct genetic causes, despite some overlap in radiographic characteristics.