Genetic Basis for Poor Lung Function Identified

Genetic Basis for Poor Lung Function Identified

An international group of researchers identified novel genetic causes for poor lung function and shared genetic causes of obstructed airflow, regardless of whether people never smoked or whether they smoked heavily, according to a study published online September 27 in the Lancet Respiratory Medicine.

"We show genome-wide evidence for shared genetic causes of low [forced expiratory volume in 1 second (FEV1)] between heavy smokers and never smokers," write Louise V. Wain, PhD, from the Department of Health Sciences, University of Leicester, United Kingdom, and colleagues. "Furthermore, our analyses suggest that smoking is only likely to interact with a small proportion of the genetic effects we have identified on lung function — that is, smoking and genetic effects generally act separately. We also show shared genetic causes of airflow obstruction between participants who reported doctor-diagnosed asthma and those who did not."

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death around the globe, and smoking tobacco was responsible for 5.1 million deaths worldwide in 2004. The authors argue that gaining a better appreciation for the genetic factors that underlie poor lung function and smoking behavior could help pinpoint better targets for future therapeutic interventions.

From March 15, 2006, to July 7, 2010, the research team selected individuals from UK Biobank, which contains data from 502,682 individuals. The authors included 50,008 unique samples representing the extremes and middle of predicted FEV1 distributions. FEV1 is among the measures used to determine airflow obstruction and to diagnose COPD.

"By sampling from the extremes of the FEV1 and smoking phenotype distributions, we identified novel associations for FEV1 and smoking behavior," Dr Wain and colleagues write. "We describe six new signals of association with FEV1 extremes, all of which were also associated with COPD using our definition based on spirometry. Five of these signals were most strongly associated with extremes of FEV1 (low vs high) in never smokers."

In an accompanying comment, Guy G. Brusselle, MD, from the Department of Respiratory Medicine, Ghent University Hospital, Belgium, and the Department of Epidemiology and the Department of Respiratory Medicine, Erasmus Medical Center, the Netherlands, and Ken R. Bracke, PhD, from the Department of Respiratory Medicine, Ghent University Hospital, note the study's numerous strengths: "[B]ig is beautiful in genetics. More than 500 000 individuals have been included in UK Biobank, and more than 50 000 individuals of European ancestry were examined in the current study on lung function genetics. Second, the investigators applied a smart sampling strategy.... Thanks to this nested case-control study design, they enriched the large sample for non-smoking participants with airflow limitation, in whom genetic risk factors are suspected to play a more important part."

Among the findings highlighted by the commentators, the study associated the nicotinic acetylcholine receptors CHRNA3 and CHRNA5 at the 15q25 locus and five novel regions of association in or near NCAM1 with nicotine addiction. They also corroborated the role of the HHIP gene in COPD susceptibility, and a passel of genes expressed in the lungs may hasten decline of lung function. Dr Brusselle and Dr Bracke suggest the findings be shored up by additional research that includes more diverse study participants.

"[W]e show the usefulness in sampling from the extremes of UK Biobank data to identify novel genetic signatures underlying phenotypes important in the development of airway disease and smoking behaviour," Dr Wain and colleagues conclude. "The ongoing genotyping, and further phenotyping, of the rest of the UK Biobank resource will facilitate further [genome-wide association studies], which will undoubtedly improve our understanding of the genetic and molecular basis of common disease."

Financial support for the study was provided by the National Institute for Health Research and the Medical Research Council, and two study authors disclosed receiving either a fellowship or grant from the Medical Research Council. Four additional authors disclosed receiving grants from Center of Excellence in Genomics, ERC, FP7, the Wellcome Trust, the University of Tartu, and a research scholar award from the Fonds de recherche Quebec–Sante. The remaining study authors and the commentators have disclosed no relevant financial relationships.

Lancet Respir Med. Published online September 27, 2015. Article full text, Comment full text

Robert Simms / Business Manager Novus Medical Inc. mobile +1- 905-407-3005 / office +1-866-926-9977 2333 Wyecroft Rd., Unit 9, Oakville, Ontario, L6L 6L4 Canada

visit for more medical innovation.