TY - JOUR
T1 - Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease
AU - Silverman, Edwin K.
AU - Palmer, Lyle J.
AU - Mosley, Jonathan D.
AU - Barth, Matthew
AU - Senter, Jody M.
AU - Brown, Alison
AU - Drazen, Jeffrey M.
AU - Kwiatkowski, David J.
AU - Chapman, Harold A.
AU - Campbell, Edward J.
AU - Province, Michael A.
AU - Rao, D. C.
AU - Reilly, John J.
AU - Ginns, Leo C.
AU - Speizer, Frank E.
AU - Weiss, Scott T.
PY - 2002
Y1 - 2002
N2 - Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV1) and the ratio of FEV1to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV1, FVC, and FEV1/FVC. In the initial genomewide scan, significant evidence for linkage to FEV1/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV1/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV1in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV1(LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV1/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.
AB - Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV1) and the ratio of FEV1to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV1, FVC, and FEV1/FVC. In the initial genomewide scan, significant evidence for linkage to FEV1/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV1/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV1in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV1(LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV1/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.
UR - http://www.scopus.com/inward/record.url?scp=18344392253&partnerID=8YFLogxK
U2 - 10.1086/340316
DO - 10.1086/340316
M3 - Article
C2 - 11914989
AN - SCOPUS:18344392253
VL - 70
SP - 1229
EP - 1239
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -