Genetic linkage and association analysis of COPD-related traits on chromosome 8p.
Genome-wide linkage analysis in the Boston Early-Onset Chronic Obstructive Pulmonary Disease (COPD) Study has demonstrated significant evidence of linkage to chromosome 8p for forced expiratory volume in 1 second, an important COPD-related phenotype. In this study, we sought to fine map the linkage peak and to test variants in two candidate genes for association with COPD and related traits. In a variance component linkage analysis on chromosome 8, including seven additional short tandem repeat markers, the logarithm of the odds of linkage score was reduced from 3.30 to 1.80 (at 1 cM). Five single nucleotide polymorphisms (SNPs) in Defensin Beta-1 (DEFB1) were genotyped in the Boston Early-Onset COPD Study families; none was significantly associated. Four SNPs and an insertion-deletion polymorphism in Macrophage Scavenger Receptor-1 (MSR1) were also genotyped in the family-based study. A coding variant (Pro275Ala) was marginally associated with two qualitative airflow obstruction traits (p < or = 0.02). This SNP showed a trend toward association in a case-control study comparing participants in the National Emphysema Treatment Trial to smoker controls (p = 0.07). Despite the reduced support for linkage upon further analysis, it remains possible that chromosome 8p contains a gene that influences COPD susceptibility. There is marginal, though not convincing, evidence for association with MSR1.
Hersh
Craig P
CP
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. craig.hersh@channing.harvard.edu
DeMeo
Dawn L
DL
Raby
Benjamin A
BA
Litonjua
Augusto A
AA
Sylvia
Jody S
JS
Sparrow
David
D
Reilly
John J
JJ
Silverman
Edwin K
EK
D000483:Alleles; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology; D019655:Quantitative Trait, Heritable; D012189:Retrospective Studies; D051117:Scavenger Receptors, Class A / Q000235:genetics*; D023083:beta-Defensins / Q000235:genetics*
C406407:DEFB1 protein, human; C495139:MSR1 protein, human; D051117:Scavenger Receptors, Class A; D023083:beta-Defensins; D004247:DNA