Progress in disease progression genetics: dissecting the genetic origins of lung function decline in COPD.

Lung function is a heritable trait. Heritability estimates posit that approximately30%–50% of the phenotypic variation in FEV1 is explained by genetics,1–3 and genome-wide association studies (GWAS) of lung function4–11 have discovered multiple genetic variants that are associated with cross-sectional measurements in adults of FEV1, FVC and FEV1/FVC ratio at genome-wide significance levels. Many of these same loci have also been implicated in GWAS of COPD. Additional work is required to link these loci to pathophysiology. Functional studies on GWAS loci involving HHIP,12 ,13 FAM13A,14 HTR4,15 AGER16 and IREB217 have already provided important insights into the biological mechanisms for genetic determinants of COPD and/or lung function.

Longitudinal change in lung function (ΔFEV1, ΔFEV1/FVC) is also heritable,18 albeit perhaps to a lesser degree than cross-sectional lung function levels. Although studies of longitudinal lung function have discovered a few loci associated with ΔFEV1 at genome-wide significance levels, none were robust to replication in the available populations. While at first glance the genetic determinants of FEV1 level and ΔFEV1 might be expected to show significant overlap, a recent study of COPD by Lange et al19 and a complementary study in asthma by McGeachie et al20 have suggested that low maximum attained lung function and accelerated lung function decline are distinct processes that can exert independent effects on the risk for chronic airflow obstruction. Therefore, it would not be surprising if different genetic determinants influenced cross-sectional and longitudinal lung function change. Longitudinal measurements of lung function are highly informative for identifying these separate processes.

Source: BMJ


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