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Original Research: COPD |

COPD Is Associated With a Macrophage Scavenger Receptor-1 Gene Sequence Variation

Jill A. Ohar, MD, FCCP; Raymond F. Hamilton, Jr, MA; Siqun Zheng, MD; Alireza Sadeghnejad, MD, PhD; David A. Sterling, PhD; Jianfeng Xu, MD, DrPH; Deborah A. Meyers, PhD; Eugene R. Bleecker; Andrij Holian, PhD
Author and Funding Information

From the Center for Human Genomics and Personalized Medicine Research, the Departments of Medicine and Pediatrics (Drs Ohar, Zheng, Sadeghnejad, Xu, Meyers, and Bleecker), Wake Forest University School of Medicine, Winston-Salem, NC; the Center for Environmental Health Sciences, the Department of Biomedical and Pharmaceutical Sciences (Mr Hamilton and Dr Holian), The University of Montana, Missoula, MT; and the Department of Environmental and Occupational Health (Dr Sterling), University of North Texas Health Science Center–School of Public Health, Fort Worth, TX.

Correspondence to: Jill A. Ohar, MD, FCCP, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: johar@wfubmc.edu


Funding/Support: Funded in part by The Selikoff Fund for Environmental and Occupational Lung Disease, Saint Louis University and by the National Center for Research Resources [P20RR017670] and the National Institutes of Environmental Health Sciences [ES-015294], both components of the National Institutes of Health.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(5):1098-1107. doi:10.1378/chest.09-1655
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Background:  Macrophages play an important role in COPD. We genotyped at-risk smokers to evaluate the role of polymorphisms in the macrophage scavenger receptor-1 gene (MSR1) in COPD susceptibility and related measures of lung function. Then, in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 single nucleotide polymorphisms (SNPs) on macrophage function by examining in vitro adhesion, receptor expression, and cell number in culture as an index of increased survival/reduced apoptosis.

Methods:  Smokers (≥ 20 pack-years) who were > 40 years (n = 714) were genotyped for seven SNPs; one nonsense change (ex6R293×_C/T), four missense changes (ex4V113A_T/C, ex4P174Y_G/T, ex11H441R_A/G, and in the ligand binding site ex6P275A_C/G), -176511_A/G in the promoter region, and IVS5-59_C/A in the intron. Nonsmoking healthy volunteers (n = 85) were genotyped, and peripheral blood monocytes were isolated from seven P275A_CG/GG and eight P275A_CC controls and cultured to generate monocyte-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a four-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 was determined by fluorescence-activated cell sorting analysis using secondary staining of antibodies against human macrophage scavenger receptor (MSR1).

Results:  The MSR1-coding SNP P275A was associated with susceptibility to COPD in smokers (P < .005) and a lower percent predicted (pp) FEV1, FEV1/FVC, and pp forced expiratory flow (FEF)25-75 (P = .03). P275A_CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression, and adhesion of macrophages to plastic in vitro (P < .05).

Conclusions:  The MSR1 association with COPD susceptibility, COPD-related measures of lung function, and abnormalities of macrophage function may account for significant COPD morbidity.

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