Editors' ChoiceLung Disease

A Protective Genetic Variant for Lungs

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Science Translational Medicine  23 Dec 2009:
Vol. 1, Issue 12, pp. 12ec43
DOI: 10.1126/scitranslmed.3000732

Diseases clearly run in families, but aside from maladies with clear Mendelian inheritance patterns, such as Huntington’s chorea, it is difficult to tell beforehand which family members will be affected. Gene-gene or gene-environment interactions are to blame for the uncertainty, but these complicating factors are extraordinarily difficult to sort out genetically, there being few well-documented examples in the literature. A new study by Hunninghake et al. reports a genetic variant that affects lung function and disease—but only in children that have asthma or in adult smokers—and gives some guidance about one way to approach this thorny problem.

The researchers knew from previous studies that a destructive protease found in the macrophages that infiltrate diseased lungs, matrix metalloproteinase-12 (MMP-12), is likely to affect lung function in general and chronic obstructive pulmonary disorder (COPD) specifically. To test whether certain MMP-12 gene variants are associated with lung function or disease, the authors studied seven independent groups of patients (a total of 8300 subjects). Two were family-based studies on children, one was a birth cohort study, and four included adult smokers and nonsmokers with and without COPD. First, they investigated the association of several single-nucleotide polymorphisms in and around MMP-12 with lung function in each of these groups and then in subsets within the groups that did or did not smoke or show lung disease. Their hunt unearthed several important conclusions.

The presence of a G rather than an A at one site in the promoter of MMP-12, a polymorphism that causes less efficient transcription of the gene, is associated with better lung function—but only in children with asthma and in adult smokers with COPD. Further, adult smokers with this gene variant have a reduced risk of getting COPD and, in one group, not having this variant increases the population’s risk of getting COPD by 28%. These associations did not exist in groups of people who had never smoked or in children without asthma.

The success of this approach can be attributed to the fact that these researchers had a high-quality candidate gene with a plausible functional involvement in lung disease. Further, the many independent groups of subjects that together generated a large sample size and that also fully represented the relevant subcategories were essential to uncovering the protective effect of this MMP-12 variant. These study characteristics allowed fruitful interrogation of subpopulations with distinct environmental or genetic influences on the endpoints of interest.

G. M. Hunninghake et al., MMP12, lung function, and COPD in high-risk populations. N Engl. J. Med. 16 December 2009 (10.1056/NEJMoa0904006). [Full Text]

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