MMP12, Lung Function, and COPD in High-Risk Populations

被引:263
作者
Hunninghake, Gary M. [1 ,2 ,3 ,4 ]
Cho, Michael H. [1 ,2 ,3 ,4 ]
Tesfaigzi, Yohannes [8 ]
Soto-Quiros, Manuel E. [9 ]
Avila, Lydiana [9 ]
Lasky-Su, Jessica [1 ,2 ,4 ]
Stidley, Chris [8 ]
Melen, Erik [1 ,2 ,4 ,10 ,14 ]
Soderhall, Cilla [11 ]
Hallberg, Jenny [15 ]
Kull, Inger [10 ]
Kere, Juha [11 ]
Svartengren, Magnus [12 ]
Pershagen, Goran [10 ]
Wickman, Magnus [10 ,13 ,15 ]
Lange, Christoph [1 ,2 ,5 ]
Demeo, Dawn L. [1 ,2 ,3 ,4 ]
Hersh, Craig P. [1 ,2 ,3 ,4 ]
Klanderman, Barbara J. [1 ,2 ,4 ]
Raby, Benjamin A. [1 ,2 ,3 ,4 ]
Sparrow, David [6 ,7 ]
Shapiro, Steven D. [16 ]
Silverman, Edwin K. [1 ,2 ,3 ,4 ]
Litonjua, Augusto A. [1 ,2 ,3 ,4 ]
Weiss, Scott T. [1 ,2 ,4 ]
Celedon, Juan C. [1 ,2 ,3 ,4 ]
机构
[1] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Ctr Genom Med, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Boston, MA USA
[5] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA
[6] Boston Univ, Sch Med, VA Normat Aging Study, VA Healthcare Syst, Boston, MA 02118 USA
[7] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA
[8] Lovelace Resp Res Inst, Albuquerque, NM USA
[9] Hosp Nacl Ninos Dr Carlos Saenz Herrera, Div Pediat Pulmonol, San Jose, Costa Rica
[10] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden
[11] Karolinska Inst, Novum, Dept Biosci, S-10401 Stockholm, Sweden
[12] Karolinska Inst, Dept Publ Hlth Sci, S-10401 Stockholm, Sweden
[13] Karolinska Inst, Ctr Allergy Res, S-10401 Stockholm, Sweden
[14] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden
[15] Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden
[16] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA
基金
英国惠康基金; 英国医学研究理事会; 瑞典研究理事会;
关键词
OBSTRUCTIVE PULMONARY-DISEASE; AIR-FLOW OBSTRUCTION; CHILDHOOD ASTHMA; POLYMORPHISMS; GENE; DECLINE; EXPRESSION; VALUES;
D O I
10.1056/NEJMoa0904006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND 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. METHODS 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. RESULTS 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=2x10(-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). CONCLUSIONS 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.
引用
收藏
页码:2599 / 2608
页数:10
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