Most previous genetic association studies of lung function have included a single cohort; reported associations with respect to specific SNPs25,26
and the direction of the associations27,28
have been inconsistently replicated in subsequent studies. A strength of our study is that it included the analysis of multiple measurements of pulmonary function in a large number of subjects29
— more than 20,000 FEV1
measurements in more than 8300 subjects.
We found that the minor allele of a SNP in MMP12 (rs2276109 [−82A→G]) was positively associated with lung function in children with asthma and in adult smokers with COPD or at risk for COPD. We also found that the minor allele of SNP rs2276109 was associated with a reduced risk of COPD in adult smokers. In the NAS cohort, the absence of the minor allele of rs2276109 was associated with a 54% increase in the risk of the onset of COPD and with a population attributable risk of COPD of 28%; the high frequency of the major (common) allele probably underlies this comparatively large risk.
The “Dutch hypothesis” states that asthma, chronic bronchitis, and emphysema are different manifestations of a disease entity that is influenced by host factors (e.g., genetic makeup) and exogenous factors (e.g., cigarette smoking).30,31
This hypothesis is supported by our findings and those of others,26,32
which suggest that certain genetic variants may play a role in the pathogenesis of both asthma and COPD.
is located on chromosome 11q22.3, in a cluster of genes encoding matrix metalloproteinases. The MMP12
SNPs associated with increased FEV1
are also associated with a delayed onset of COPD and a reduced risk of COPD. SNP rs2276109 is a functional polymorphism whose minor allele (G) has been associated with decreased promoter activity through less efficient binding of AP-1 in both murine and human monocytic cell lines.24
Deletion of the AP-1 binding site abolishes both basal and stimulated expression of MMP12
Thus, our findings are consistent with a beneficial role of reduced MMP12
expression in pulmonary function and the pathogenesis of COPD in humans.
In the NAS cohort, the minor allele of rs2276109 was associated with increased FEV1
but not with the rate of decline in lung function. Similarly, there was no association between two SNPs in MMP12
and the rate of decline in lung function in the Lung Health Study (NCT00000568).34
Although associations between haplotypes, including a SNP in MMP12,
and a decline in lung function were reported in this study, the associations were inconsistent in direction and were not replicated in other cohorts.35
Our results suggest that variants of MMP12
are determinants of the level of lung function in subjects who are at risk for airflow obstruction (e.g., persons with asthma and smokers).
Our study has several limitations. First, we observed significant associations for rs2276109 in combined analyses, but these findings were not uniformly significant in each of the cohorts analyzed. This may be related to attenuated effects of this SNP in low-risk cohorts (e.g., those that included persons without asthma), false negative results due to small samples (e.g., in NETT35
), or potential effects of medication (e.g., in CAMP).
Second, ascertainment bias may have negatively influenced our analysis of FEV1
in CAMP and NETT, since both studies excluded subjects on the basis of increased disease severity (in the case of CAMP and NETT) or reduced disease severity (in the case of NETT), as defined according to FEV1
In addition to differences in geographic factors and ancestral history between the GACRS and CAMP cohorts, there may have been differences in exposure to allergens. Costa Ricans are exposed to high levels of dust-mite allergens,36
a factor that may be relevant, since exposure to dust-mite allergens can lead to the release of proinflammatory cytokines through an AP-1–dependent pathway.37
Third, our results for rs737693 and rs2276109 should be viewed as a single finding, since these SNPs are in tight linkage disequilibrium (r2
>90%) in all the cohorts that were analyzed. Although we suspect that our results are explained primarily by variation within the AP-1 binding site of the MMP12
promoter (rs2276109), variants in the 3′ genomic region of MMP12
(rs737693) could represent an alternative or additional explanation for our findings. Binding sites within a 3′ genomic region have been shown to influence the transcription of another matrix metalloproteinase.38
Although we did not test SNPs in all genes adjacent to MMP12
, our negative results for MMP3
and the linkage-disequilibrium patterns for the MMP12
region in the HapMap (Fig. 1 in the Supplementary Appendix) suggest that our results are due to variation in MMP12
. There was no association between SNPs in linkage disequilibrium with rs2276109 and FEV1
in adults in the British Birth Cohort, which is consistent with our negative findings with respect to an association between rs2276109 and FEV1
in subjects without asthma and in persons who never smoked. However, additional findings of an association between MMP12
SNPs and FEV1
in the British Birth Cohort suggest that there could be additional susceptibility variants for lung function in MMP12
Finally, caution should be exercised in interpreting the population attributable risks from our analyses. Although our findings strongly suggest that MMP-12 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 (which is consistent with previous findings with respect to the predictive capacity of replicated genetic associations).40
In summary, our findings suggest that the minor allele of SNP rs2276109 in MMP12 is associated with lung function in children with asthma and adult smokers, as well as with the risk of COPD in adult smokers.