Smoking, lung function, and the genetics that explain it

By: David Shifrin, PhD Science Writer, Filament Life Science Communications

The percentage of smokers in the United States declined by almost 15% between 2005 and 2013 (the latest date for which survey results are available), from 20.9% to 17.8% of adults (cdc.gov). However, that still leaves more than 40 million adults who are active smokers. In the UK, according to Action on Smoking and Health, 10 million adults smoke.

Cessation efforts and education have certainly made their mark, but smoking remains a significant cause of health problems and increased mortality. Globally, COPD is the third leading cause of death.

Of course, there is a wide range in response to tobacco smoke. Some smokers experience few related health problems and survive well into old age, while others who are merely exposed to occasional second-hand smoke suffer serious effects. In order to better understand the genetic etiology of lung disease and smoking, researchers from the Universities of Nottingham and Leicester combed through information from 50,000 participants in UK Biobank.

The power of this study was both in the large number of samples and the type of data collected. Importantly, biological samples were collected during recruitment (2006-2010), as was physiological data, including forced expiratory volume (FEV, the volume of air that an individual can push out) to give a readout on lung function. This combination of data positioned the study to make significant findings because “[no] other biobank with spirometry data and DNA as large as UK Biobank [was available].”

Genotyping and subsequent filtering resulted in ~28.5 million variants across 49,000 individuals included in the study (about 1,000 of the original 50,000 were eliminated for quality control reasons). Again, these numbers serve to demonstrate the extensiveness of this study and its resulting statistical power.

Analysis of these variants revealed that low FEV is polygenic, with the accumulation of many “variants of individually small effect size” leading to the condition. Additionally, among the individuals with low FEV, a substantial number of variants were consistent across both smokers and non-smokers. This indicated that low volume is a genetic condition at least somewhat independent of lifestyle. Additionally, several signals were associated with COPD and extreme FEV (either high or low). Perhaps even more importantly, the results indicated that smoking (probably) does not significantly affect genes implicated in low FEV. Thus, “smoking and genetic effects generally act separately.”

Genetic mapping also identified five novel loci implicated in a predisposition to smoking. Much of the genetic mapping throughout this study was carried out on regions already known to be involved in lung function. As a result, the more detailed array used by the UK team was able to highlight specific loci pulled from these regions. One of the genes associated with smoking encodes a cell adhesion protein that is expressed in the brain. It will be interesting to see future cellular and in vivo studies that investigate the molecular processes this protein is involved in that could provide insight into behavior/addiction such as smoking.

Using a relatively large sample size and detailed genetic mapping, this study outlined genetic factors that help to explain why some smokers don’t suffer adverse effects while others have significant health problems. Although the smoking-associated signals and low FEV signals appear to be independent, individuals with both could be at greater risk. The same holds true for the COPD-associated genes.

The hope is that this information will eventually lead not just to an understanding of the genes involved in smoking and general lung health, but also to developing therapeutics or behavioral interventions to help smokers quit before incurring problems. Based on the fact that neuronal-specific genes were found in the study, this hope seems reasonable.