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 (> or = 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 smokers (P < .005) and a lower percent predicted (pp) FEV(1), 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 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.
authors.affiliation: Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA. johar@wfubmc.edu
authors.forename: Jill A
authors.initials: JA
authors.lastname: Ohar
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Hamilton
authors.forename: Siqun
authors.initials: S
authors.lastname: Zheng
authors.forename: Alireza
authors.initials: A
authors.lastname: Sadeghnejad
authors.forename: David A
authors.initials: DA
authors.lastname: Sterling
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.forename: Andrij
authors.initials: A
authors.lastname: Holian
mesh_terms: D016022:Case-Control Studies; D002448:Cell Adhesion / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008168:Lung / Q000503:physiopathology; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology; D051117:Scavenger Receptors, Class A / Q000235:genetics*; D012907:Smoking; D014797:Vital Capacity / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; C495139:MSR1 protein, human; D051117:Scavenger Receptors, Class A