COPD is associated with a macrophage scavenger receptor-1 gene sequence variation

Jill A. Ohar, Raymond F. Hamilton, Siqun Zheng, Alireza Sadeghnejad, David Sterling, Jianfeng Xu, Deborah A. Meyers, Eugene R. Bleecker, Andrij Holian

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Abstract

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 (ex6R293x-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 smoklt;.005) and a lower percent predicted (pp) FEV1, FEV 1/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 vilt;.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.

Original languageEnglish
Pages (from-to)1098-1107
Number of pages10
JournalChest
Volume137
Issue number5
DOIs
StatePublished - 1 May 2010

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Scavenger Receptors
Chronic Obstructive Pulmonary Disease
Macrophages
Genes
Single Nucleotide Polymorphism
Cell Count
Apoptosis
Lung
Survival
Genetic Promoter Regions
Trypsin
Introns
Plastics
Monocytes
Healthy Volunteers
Flow Cytometry
Binding Sites
Genotype
Maintenance
Tissue Donors

Cite this

Ohar, J. A., Hamilton, R. F., Zheng, S., Sadeghnejad, A., Sterling, D., Xu, J., ... Holian, A. (2010). COPD is associated with a macrophage scavenger receptor-1 gene sequence variation. Chest, 137(5), 1098-1107. https://doi.org/10.1378/chest.09-1655
Ohar, Jill A. ; Hamilton, Raymond F. ; Zheng, Siqun ; Sadeghnejad, Alireza ; Sterling, David ; Xu, Jianfeng ; Meyers, Deborah A. ; Bleecker, Eugene R. ; Holian, Andrij. / COPD is associated with a macrophage scavenger receptor-1 gene sequence variation. In: Chest. 2010 ; Vol. 137, No. 5. pp. 1098-1107.
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title = "COPD is associated with a macrophage scavenger receptor-1 gene sequence variation",
abstract = "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 (ex6R293x-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 smoklt;.005) and a lower percent predicted (pp) FEV1, FEV 1/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 vilt;.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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Ohar, JA, Hamilton, RF, Zheng, S, Sadeghnejad, A, Sterling, D, Xu, J, Meyers, DA, Bleecker, ER & Holian, A 2010, 'COPD is associated with a macrophage scavenger receptor-1 gene sequence variation', Chest, vol. 137, no. 5, pp. 1098-1107. https://doi.org/10.1378/chest.09-1655

COPD is associated with a macrophage scavenger receptor-1 gene sequence variation. / Ohar, Jill A.; Hamilton, Raymond F.; Zheng, Siqun; Sadeghnejad, Alireza; Sterling, David; Xu, Jianfeng; Meyers, Deborah A.; Bleecker, Eugene R.; Holian, Andrij.

In: Chest, Vol. 137, No. 5, 01.05.2010, p. 1098-1107.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - COPD is associated with a macrophage scavenger receptor-1 gene sequence variation

AU - Ohar, Jill A.

AU - Hamilton, Raymond F.

AU - Zheng, Siqun

AU - Sadeghnejad, Alireza

AU - Sterling, David

AU - Xu, Jianfeng

AU - Meyers, Deborah A.

AU - Bleecker, Eugene R.

AU - Holian, Andrij

PY - 2010/5/1

Y1 - 2010/5/1

N2 - 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 (ex6R293x-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 smoklt;.005) and a lower percent predicted (pp) FEV1, FEV 1/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 vilt;.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.

AB - 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 (ex6R293x-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 smoklt;.005) and a lower percent predicted (pp) FEV1, FEV 1/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 vilt;.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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DO - 10.1378/chest.09-1655

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JO - Chest

JF - Chest

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Ohar JA, Hamilton RF, Zheng S, Sadeghnejad A, Sterling D, Xu J et al. COPD is associated with a macrophage scavenger receptor-1 gene sequence variation. Chest. 2010 May 1;137(5):1098-1107. https://doi.org/10.1378/chest.09-1655