COPD Is Associated With a Macrophage Scavenger Receptor-1 Gene Sequence Variation
COPD Is Associated With a Macrophage Scavenger Receptor-1 Gene Sequence Variation
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DOI：
10.1378/chest.09-1655
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发表时间：
2010-05-01
期刊：
影响因子：
9.6
通讯作者：
Holian, Andrij
中科院分区：
文献类型：
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作者：
Ohar, Jill A.;Hamilton, Raymond E., Jr.;Holian, Andrij
背景：巨噬细胞在COPD中起重要作用。我们对高危吸烟者进行基因分型，以评估巨噬细胞清道夫受体-1基因（MSR1）多态性在COPD易感性和肺功能相关指标中的作用。然后，在具有特定MSR1基因型的供体巨噬细胞中，我们通过检测体外粘附、受体表达和培养细胞数量作为增加存活/减少凋亡的指标，来确定MSR1单核苷酸多态性（snp）对巨噬细胞功能的影响。方法：吸烟者（>= 20包年）>40岁（n = 714）进行7个snp基因分型；1个无义变化（ex6R293x_C/T）， 4个错义变化（ex4V113A_T/C, ex4P174Y_G/T， ex11H441R_A/G和配体结合位点ex6P275A_C/G），启动子区域-176511_A/G，内含子IVS5-59_C/A)。对85名不吸烟的健康志愿者进行基因分型，并从7名P275A_CG/GG和8名P275A_CC对照中分离外周血单核细胞，培养产生单核细胞源性巨噬细胞（MDM）。胰蛋白酶和刮痧去除MDM的有效性评分为4分主观量表。用Z1粒子计数器计数MDM，用抗人巨噬细胞清除受体（human macrophage scavenger receptor, MSR1）抗体二次染色荧光活化细胞分选分析测定MSR1的表面表达。结果：msr1编码SNP P275A与吸烟者COPD易感性相关（P < 0.005），预测FEV1、FEV1/FVC和pp用力呼气流量（FEF）的比例较低（25-75）（P = 0.03）。P275A_CG/GG还与体外培养细胞维持数量（增加存活/减少凋亡）、MSR1表达和巨噬细胞对塑料的粘附增加有关（P < 0.05）。结论：MSR1与COPD易感性、COPD相关肺功能指标和巨噬细胞功能异常相关，可能是COPD发病率的重要原因。胸部2010;137 (5): 1098 - 1107
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 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. CHEST 2010; 137(5):1098-1107