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Genome-wide Linkage of Forced Mid-expiratory Flow in Chronic Obstructive Pulmonary Disease

Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Dawn L. DeMeo, M.D., M.P.H., Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. Email: redld{at}channing.harvard.edu

Familial aggregation of forced expiratory flow during the middle half of the FVC (FEF_25–75%) and FEF_25–75%/FVC has been observed in the Boston Early-Onset Chronic Obstructive Pulmonary Disease 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 chronic obstructive pulmonary disease, and linkage analyses of FEF_25–75% and FEF_25–75%/FVC were performed using Sequential Oligogenic Linkage Analysis Routines. There was suggestive evidence for linkage of FEF_25–75%/FVC with chromosome 2 (LOD 2.60 at 216 cM). In a smokers-only analysis, evidence for linkage was observed for postbronchodilator FEF_25–75% with chromosome 12 (LOD 5.03 at 35 cM) and chromosomes 2 and 12 for FEF_25–75%/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 36 cM). Our analyses provide evidence for linkage of FEF_25–75% and FEF_25–75%/FVC on chromosomes 2q and 12p. LOD scores of greater than two 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: chronic obstructive pulmonary disease • genetics • linkage mapping • pulmonary disease • smoking

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