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Am J Respir Crit Care Med. 2004 Dec 15;170(12):1294-301. Epub 2004 Sep 3.

Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease.

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  • 1Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.


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 FEV(1)/FVC on chromosome 2 (LOD 4.13 at 229 cM) and FEV(1) 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.

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