MMP12, lung function, and COPD in high-risk populations.
MMP12, lung function, and COPD in high-risk populations.
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DOI：
10.1056/nejmoa0904006
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发表时间：
2009-12-31
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影响因子：
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通讯作者：
Celedón JC
中科院分区：
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作者：
Hunninghake GM;Cho MH;Tesfaigzi Y;Soto-Quiros ME;Avila L;Lasky-Su J;Stidley C;Melén E;Söderhäll C;Hallberg J;Kull I;Kere J;Svartengren M;Pershagen G;Wickman M;Lange C;Demeo DL;Hersh CP;Klanderman BJ;Raby BA;Sparrow D;Shapiro SD;Silverman EK;Litonjua AA;Weiss ST;Celedón JC
影响儿童和成人肺功能的遗传变异可能最终导致慢性阻塞性肺疾病（COPD）的发展，特别是在高危人群中。我们测试了编码基质金属蛋白酶12 （MMP12）基因的单核苷酸多态性（snp）与肺功能测量（支气管扩张剂前1秒用力呼气量[FEV1]）之间的关联，研究对象包括儿童和成人在内的7个队列的8300多名受试者。在规范衰老研究（NAS）中，一组最初健康的成年男性，我们测试了与FEV1相关的snp与COPD发病时间之间的关联。然后，我们在两组患有COPD或有COPD风险的成年人中检查了MMP12 snp与COPD之间的关系。MMP12启动子区域功能变异的次要等位基因(G) （rs2276109[−82A→G]）与FEV1呈正相关（P=2×10−6）。该等位基因还与NAS队列中COPD发病风险降低相关（风险比，0.65；95%可信区间[CI]， 0.46 ~ 0.92; P = 0.02），与吸烟者队列中COPD发病风险降低相关（优势比，0.63;95% CI, 0.45 ~ 0.88; P = 0.005），与早发性COPD家庭研究参与者中COPD发病风险降低相关（P = 0.006）。MMP12中一个SNP的小等位基因（rs2276109）与哮喘儿童和吸烟成人肺功能的积极影响有关。该等位基因也与成年吸烟者患慢性阻塞性肺病的风险降低有关。
Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups. We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV1]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV1 and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD. The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [−82A→G]) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006). The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.