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GWAS Yields New Loci Linked to Lung Function, Smoking Behavior

NEW YORK (GenomeWeb) – Researchers have discovered genetic variants that appear to influence a range of lung-related traits — from lung function and chronic obstructive pulmonary disease (COPD) risk to smoking behavior.

The genome-wide association study, led by scientists at the University of London, the University of Leicester, and the University of Nottingham, was published online in Lancet Respiratory Medicine last night.

Based on genotyping data for tens of thousands of individuals recruited to the UK Biobank project between 2006 and 2010, the team performed a genome-wide association study focusing on extreme lung traits. Included in the analysis were individuals with low, medium, or high expiratory lung volumes, heavy smokers and never smokers, individuals with or without asthma, and those with varying COPD severity.

In the process, the researchers found half a dozen loci with new or known ties to high or low forced expiratory lung volumes. Those with low 'forced expiratory volume in one second,' or FEV1, values tended to share genetic variants, they noted, regardless of individuals' smoking history or asthma diagnoses. Expiratory volume-associated variants often overlapped with risk variants for COPD as well, while smoking behavior was linked to variants at five new loci.

"These results provide new insight into the specific mechanism underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction … irrespective of smoking behavior and other airway disease," senior authors David Strachan, Martin Tobin, and Ian Hall and their colleagues wrote.

Their findings are slated to be presented at the annual European Respiratory Society meeting in Amsterdam this week.

Although smoking and air pollution have been implicated in COPD risk, both COPD and smoking behavior appear to have heritable components, the researchers explained. To explore the genetics of lung health and smoking behavior in more detail, they tapped into samples from more than 500,000 UK Biobank participants.

Using a custom Affymetrix array targeting common, low frequency, and rare variants in the UK population, the team genotyped 50,008 samples for a nested case-control study that was done as part of the UK Biobank Lung Exome Variant Evaluation (BiLEVE) effort.

Coupled with FEV1 data from spirometry-based measurements of UK Biobank participants, the genotyping data made it possible to search for associations with extremely low, extremely high, or middle-of-the-road forced expiratory volumes, along with asthma diagnoses, COPD, and self-reported smoking behaviors.

From data for 25,004 never smokers with low FEV1, average FEV1, or high FEV1, and as many heavy smokers from each group, the team saw extreme FEV1 associations for new variants at two known loci — sites in and around the chromosome 4 gene NPNT and the HLA-DQB1 and HLA-DQA2 genes on chromosome 6.

The analysis also uncovered four new FEV1-asssociated loci neighboring the KANSL1, TSEN54, TET2, and RBM19/TBX5 genes. All six of the sites also seemed to show overlapping ties to COPD risk.

Most of the associations were slightly stronger in never smokers with low FEV1, the researchers noted, though a rare variant falling between RBM19 and TBX5 had more pronounced ties to low FEV1 in heavy smokers.

The team's rare variant analysis uncovered a chromosome 12 variant that was linked to FEV1 in smokers after adjustment for pack years, while a chromosome 17 variant led the group to a duplication-containing inversion that was associated with FEV1 in both never smokers and heavy smokers.

The latter duplication involved part of a gene coding for a histone acetyltansferase complex component, the researchers explained, hinting at a potential epigenetic effect at this site.

When the researchers focused on smoking behavior, meanwhile, they found five new and four known linked loci that differed between never smokers and heavy smokers. 

The study's authors noted that more work is needed to tease apart the biology behind the associations they identified and to better understand and treat COPD and other forms of lung disease, as well as nicotine addiction.