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

Familial aggregation of forced expiratory flow during the middle half of the FVC (FEF25-75%) and FEF25-75%/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 FEF25-75% and FEF25-75%/FVC were performed using Sequential Oligogenic Linkage Analysis Routines. 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 postbronchodilator 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 36 cM). Our analyses provide evidence for linkage of FEF25-75% and FEF25-75%/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.