A mutation in a macrophage-derived protein helps preserve lung function in children with asthma and in adult smokers and also affords protection against chronic obstructive pulmonary disease, according to data from a large cohort study.
Found in the promoter region of matrix metalloproteinase 12 (MMP12), the single-nucleotide polymorphism (SNP) had a positive impact on FEV1 in asthmatic children and in current and former smokers in a combined analysis of all cohorts included in the study.
The protection against COPD applied to specific cohorts included in the overall analysis, according to an online report in the New England Journal of Medicine.
The study’s design provides support for the findings that previous studies could not, the authors noted.
“Most previous genetic association studies of lung function have included a single cohort; reported associations with specific SNPs and the direction of the associations have been inconsistently replicated in subsequent studies,” Juan Celedon, MD, DrPH, of Harvard, and colleagues wrote.
“A strength of our study is that it included the analysis of multiple measurements of pulmonary function in a large number of subjects — more than 20,000 FEV1 measurements in more than 8,300 subjects.”
The results support the so-called “Dutch hypothesis” that asthma and COPD are different manifestations of the same disease, Guy G. Brusselle, MD, PhD, of Ghent University Hospital in Belgium, wrote in an accompanying editorial.
Produced by macrophages, MMP12 is the predominant “patroller” cell in the lower airways under normal conditions and the principal inflammatory cell recruited in response to smoking, the authors said.
In laboratory mice, MMP12 is necessary for development of emphysema in response to cigarette smoke. However, the role of MMP12 in human emphysema remains unclear.
Measures of pulmonary function throughout life have a strong correlation, suggesting that factors that determine lung function in childhood might also influence the risk of COPD in adults.
“We hypothesized that variants in MMP12 influence lung function and are risk factors for COPD, particularly in groups that are at risk for reduced lung function,” the authors wrote.
To test the hypothesis, they explored potential associations between SNPs in MMP12 and lung function measures (FEV1) in seven cohorts, including participants in two family-based studies of children with asthma, in one birth-cohort study, and in four cohorts of adults with and without COPD.
The seven cohorts comprised 8,300 participants.
The genetic testing showed that the minor allele (G) of a functional variant in the promoter region of MMP12 had a positive association with FEV1 in a combined analysis of children with asthma and of current and former smokers in all of the cohorts (P=2×10-6). The same allele also was associated with a reduced risk of COPD in:
- Current and former smokers in one cohort (HR 0.65, 95% CI 0.46 to 0.92, P=0.02) — but not in people who had never smoked
- A cohort of smokers (OR 0.63, 95% CI 0.45 to 0.88, P=0.005)
- Participants in a family-based study of early-onset COPD (P=0.006)
“Caution should be exercised in interpreting the population attributable risks from our analyses,” the authors wrote.
“Although our findings strongly suggest that MMP12 has a role in determining lung function and susceptibility to COPD in high-risk groups, knowledge of the genotype for an MMP12 variant does not add to clinical variables in predicting the onset of COPD.”
In the editorial, Brusselle said the study has “revitalized the Dutch hypothesis and set the scene for future genetic studies of chronic obstructive airway disease.”
The following disclosures were reported by the authors: Lydiana Avila, AstraZeneca and Merck; Juha Kere, Johnson & Johnson; Christoph Lange, Golden Helix; Benjamin A. Raby, Novartis; Edwin K. Silverman, AstraZeneca and GlaxoSmithKline; Manuel E. Soto-Quiros, AstraZeneca, GlaxoSmithKline, and Merck; Magnus Svartengren, Sandvik Hand Materials; Yohannes Tesfaigzi, Sepracor; Scott T. Weiss, Genentech; Magnus Wickman, Phadia and Merck.
Brussell’s disclosures are available at www.nejm.org.