MMP12, lung function, and COPD in high-risk populations

Abstract

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 [FEV(1)]) 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 FEV(1) 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 FEV(1) 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.

Trial registration: ClinicalTrials.gov NCT00000575 NCT00000606.

Figure 1. Results of Analyses of the Association between SNPs in or near MMP12 and FEV₁

The upper portion of the figure shows the results of the analyses of an association between prebronchodilator forced expiratory volume in 1 second (FEV₁) and all single-nucleotide polymorphisms (SNPs) genotyped in subjects in the Genetics of Asthma in Costa Rica Study (GACRS) and between prebronchodilator FEV₁ and relevant SNPs in subjects in the Childhood Asthma Management Program (CAMP); the Children, Allergy, Milieu, Stockholm Epidemiological Survey (BAMSE); the Boston Early-Onset COPD (eoCOPD) study; the National Emphysema Treatment Trial (NETT); the Lovelace Smokers Cohort (Lovelace); and the Normative Aging Study (NAS). P values for combined analyses were calculated with the use of Fisher's method. The bottom portion of the figure shows the pairwise (r²) linkage-disequilibrium patterns for the genotyped region in the Centre d'Etude du Polymorphisme Humain (CEPH) population and in the GACRS and CAMP parents. The red lines show the similarity in the linkage-disequilibrium patterns for rs737693 and rs2276109 in parents in CEPH trios in HapMap, GACRS, and CAMP.

Figure 2. Proportion of Subjects without COPD, According to Genotype and According to Smoking Status and Genotype

Estimated survival curves from Cox proportional-hazard regression models are shown for the Normative Aging Study (NAS) cohort. Panel A shows the estimated survival curves with subjects stratified according to the genotype for the single-nucleotide polymorphism (SNP) rs2276109 — subjects who were homozygous for the major allele of SNP rs2276109 and subjects who had at least one copy of the minor allele for SNP rs2276109. Panel B shows the estimated survival curves with subjects stratified according to current smoking status and genotype — subjects who were former smokers or who had never smoked and who were homozygous for the major allele of SNP rs2276109; subjects who were former smokers or who had never smoked and who had at least one copy of the minor allele for SNP rs2276109; current smokers who were homozygous for the major allele of SNP rs2276109; and current smokers with at least one copy of the minor allele for SNP rs2276109.