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Genetic variation and susceptibility to COPD

Posted Dec 29 2009 12:00am

The Dec. 17 New England Journal of Medicine has an interesting article exploring genetic susceptibility to COPD.   Having just recently finished my lung pathology course to second-year medical students, I can confess to the awkward feeling I have when the inevitable question arises as to why doesn't everyone who smokes get COPD (or lung cancer, for that matter).  My (somewhat feeble) reply is to ascribe this to "individual differences" or "genetic variation."  This paper tries to investigate specifically how genetic variation might be with associated with susceptibility to COPD.

The rationale for the study is that matrix metalloproteinase-12, produced by alveolar macrophages, is essential for the development of emphysema in mouse models and is increased by up to a factor of 9 in alveolar macrophages from smokers compared to non-smokers.  Further, production of MMP12 in lower airways leads to destruction of elastic fibers in alveolar walls--the resulting increase in elastin fragments recruits more macrophages thus setting up a reinforcing feedback loop that amplifies this process.  The authors' hypothesis is that MMP12 variants influence lung function and the development of COPD.  Their study tested for an association between SNPs in MMP12 and lung function test (FEV1) in different cohorts including children with asthma and adults with and without COPD.

They found a positive association between the minor allele of SNP rs2276109 and FEV1 in all cohorts and, in adult cohorts, a 35% reduction in the risk of developing COPD in smokers.  Conversely, they observed a 54% increased in risk of COPD in smokers in the absence of the minor allele (i.e. homozygous for the major allele).  It is noted that the minor allele of SNP rs2276109 is a functional polymorphism is associated with decreased promoter activity through less efficient binding of AP-1 in murine and human monocytic cell lines.  Further, deletion of the AP-1 binding site abrogates both baseline and stimulated MMP12 expression.  There are some important limitations to this study but this is a fascinating insight into "individual variation" due to genetic variability in SNPs and an association between smoking and the development of COPD.

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