Genetic Variant, Independent of Smoking, Is Risk Factor for COPD
A single alteration in the sequence of the CHRNA5 gene that leads to inflammation, tissue remodeling, and abnormal repair of airway cells was found, in a recent study, to be a risk factor for chronic obstructive pulmonary disease (COPD).
Notably, this gene variant is involved in nicotine-responding/dependent pathways, but was found to not be linked with smoking, the study shows.
The changes caused by the gene alteration, observed in mouse models and human nasal samples, were associated with an increased susceptibility to environment-related stress leading to lung impairment.
“This gene version appears to be a genetic predisposing factor for the disease independent of smoking,” Philippe Birembaut, one of the study’s co-senior authors, of the University of Reims Champagne-Ardenne, in France, said in a press release.
“COPD onset then occurs subsequent to repeated lesions of airway tissue caused by other molecules including atmospheric pollutants,” Birembaut said.
The researchers now plan to “define the characteristics of COPD patients carrying this mutation in order to develop personalized medicine,” said Uwe Maskos, another of the study’s co-senior authors and head of the integrative neurobiology of cholinergic systems unit at the Institut Pasteur, in Paris.
The study, “An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions,” was published in the journal Nature Communications.
COPD is characterized by excessive airway inflammation, oxidative stress, abnormal repair and remodeling of the lung epithelium — the tissue that lines the airways — and scarring that lead to permanent lung damage. Oxidative stress is a type of cellular damage resulting from an imbalance between the production of potentially harmful oxidant molecules and the cells’ ability to clear them through antioxidants.
The disease is caused mainly by repeated lesions due to long-term exposure to irritants, such as cigarette smoke, air pollution, and chemical gases.
Previous studies showed that changes in genes providing instructions for making subunits of the nicotinic acetylcholine receptor (nAChR) were associated with both smoking and COPD.
nAChR, a channel protein located at the cell surface, controls the entry of various ions into the cell and is activated by acetylcholine, a brain chemical messenger, and nicotine, the addictive substance found in tobacco products. The receptor is found not only in the brain, but also in other tissues, such as the airways.
However, “it is unclear whether the associations between [these genetic variants] and COPD are solely due to smoking,” the researchers wrote.
Now, Birembaut, Maskos, and colleagues in France, the U.S., and Canada, provided evidence that one such variant — located in CHRNA5, the gene coding for nAChR’s alpha5 subunit — promotes the development of COPD-like features regardless of smoking exposure.
This mutation, called rs16969968, comprises a single nucleotide change in the gene’s sequence that results in an amino acid switch in the resulting subunit protein. Nucleotides are the basic units of DNA and amino acids are the building blocks of proteins.
Notably, rs16969968 is present in 37% of the European population and at even higher frequencies in Middle Eastern populations.
The team first examined the effects of this variant on a mouse model containing the rs16969968 mutation and producing the mutated alpha5 subunit specifically on airway cells.
This genetic variation was found to be associated with spontaneous airway epithelium inflammation and remodeling. Notably, these mice eventually developed emphysema, a severe form of COPD characterized by gradual destruction of alveoli — the tiny air sacs within the lungs that play a key role in gas exchange.
Also, exposure to oxidative stress and emphysema-promoting molecules significantly amplified airway defects in these mice, relative to healthy mice, highlighting that this mutation increases the susceptibility to COPD-like features and is a risk factor.
Further analyses in these mice, as well as in lab-grown human cells, revealed that production of the mutated alpha5 subunit in airway epithelial cells led to the production of pro-inflammatory molecules, airway remodeling, and abnormal repair and increased growth of airway basal cells. Basal cells are responsible for epithelial renewal.
These deficits were found to be associated with reduced calcium entry into cells, increased activity of signaling pathways involved in cell growth, and higher levels of TNF-alpha — a pro-inflammatory molecule involved in wound repair and implicated in COPD.
The damaging effects of the rs16969968 mutation also were confirmed in samples of nasal polyps removed from 123 non-smoking, healthy people with and without this genetic variation. Most (68.3%) of them carried the mutation in either one or both copies of the gene, while 39 (31.7%) did not have the mutation.
Nasal polyps are non-cancerous growths inside the nose lined by an airway-like epithelium, thereby representing a relevant model of human airway cells.
Analysis of these samples showed that the presence of rs16969968 was significantly associated with inflammation, abnormal cell growth, and global epithelial remodeling.
“We provide here the first functional link considering the clinical association of [rs16969968] with COPD,” the researchers wrote.
These findings highlight that rs16969968 “directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target,” they added.
The team now plans to explore the role of this genetic variation in COPD patients considering their smoking status.
“Understanding [rs16969968] contribution to airway remodeling and inflammation may help elucidating the [underlying mechanisms] and represent a target for preventing and limiting COPD,” the researchers concluded.