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Human Molecular Genetics, 2002, Vol. 11, No. 6 623-632
© 2002 Oxford University Press

Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes

Edwin K. Silverman1,2,4,+, Jonathan D. Mosley1, Lyle J. Palmer1,4, Matthew Barth1, Jody M. Senter1, Alison Brown1, Jeffrey M. Drazen2,4, David J. Kwiatkowski4, Harold A. Chapman6, Edward J. Campbell5, Michael A. Province7, D. C. Rao7, John J. Reilly2,4, Leo C. Ginns3,4, Frank E. Speizer1,4 and Scott T. Weiss1,4

1Channing Laboratory and 2Division of Pulmonary and Critical Medicine, Department of Medicine, Brigham and Women’s Hospital, 3Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, 4Harvard Medical School, Boston, MA, USA, 5Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA, 6Division of Pulmonary and Critical Care Medicine, University of California at San Francisco, San Francisco, CA, USA and 7Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe {alpha}1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV1) < 60% predicted, FEV1/FVC < 90% predicted], mild airflow obstruction (FEV1 < 80% predicted, FEV1/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD.

+ To whom correspondence should be addressed at: Channing Laboratory, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 617 525 0856; Fax: +1 617 525 0958; Email: ed.silverman@channing.harvard.edu


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