Published ahead of print on September 3, 2004, doi:10.1164/rccm.200404-524OC
Am. J. Respir. Crit. Care Med., Volume 170, Number 12, December 2004, 1294-1301
A more recent version of this article appeared on December 15, 2004
Submitted on April 21, 2004
Accepted on August 28, 2004
Genomewide Linkage of Forced Mid-expiratory Flow in Chronic Obstructive Pulmonary Disease
Dawn L DeMeo1*, Juan C Celedon2, Christoph Lange3, John J Reilly4, Harold A Chapman5, Jody S Sylvia6, Frank E Speizer7, Scott T Weiss7, and Edwin K Silverman1
1 Channing Laboratory, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA,
2 Channing Laboratory, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA,
3 Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA,
4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA,
5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA,
6 Channing Laboratory, Boston, MA, USA,
7 Channing Laboratory, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: redld{at}channing.harvard.edu.
Familial aggregation of forced expiratory flow at the mid-portion of forced vital capacity (FEF25-75) and FEF25-75/forced vital capacity (FVC) has been observed in the Boston Early-Onset Chronic Obstructive Pulmonary Disease (COPD) Study, but linkage results have not been reported for these phenotypes. An autosomal whole genome-wide linkage scan was performed in 72 pedigrees ascertained through a proband with severe, early-onset COPD and linkage analyses of FEF25-75 and FEF25-75/FVC were performed using SOLAR. There was suggestive evidence for linkage of FEF25-75/FVC with chromosome 2 (LOD 2.60 at 216 cM). In a smokers-only analysis, evidence for linkage was observed for post-bronchodilator FEF25-75 with chromosome 12 (LOD 5.03 at 35 cM) and chromosomes 2 and 12 for FEF25-75/FVC (LOD 4.12 at 221 cM and LOD 3.46 at 35 cM respectively); in the smokers-only model evidence for linkage also was robust for FEV1/FVC on chromosome 2 (LOD 4.13 at 229 cM) and FEV1 on chromosome 12 (LOD 3.26 at 36cM). Our analyses provide evidence for linkage of FEF25-75 and FEF25-75/FVC on chromosomes 2q and 12p. LOD scores greater than 2 were also observed for chromosomes 16, 20 and 22 with the smokers-only analysis, which may suggest gene-by-smoking interactions in these regions.
Key words: pulmonary disease, linkage mapping, smoking, COPD, genetics
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