Cystic fibrosis (CF) patients and carriers — those with mutations in only one copy of the CFTR, the gene associated with CF — of European ancestry are at a higher risk of developing pneumonia, according to a U.S. study of genetic risk for this lung disease.
CF patients were also found to be at an increased risk of more severe pneumonia.
“This study is so important because we performed analyses separately in participants of Caucasian ancestry as well as African ancestry to identify genetic risk factors contributing to pneumonia susceptibility and severity,” Jennifer Below, PhD, the study’s senior author and an associate professor of medicine at Vanderbilt University Medical Center (VUMC), in Nashville, said in a university press release.
The findings may help in identifying patients more susceptible to pneumonia caused by a number of triggers, including COVID-19 infection, and in starting early approaches that might prevent more severe disease, the researchers noted.
Pneumonia is a potentially life-threatening disease in which the small air sacs in the lungs become inflamed and fill with fluid or pus, potentially leading to respiratory failure and death. It is a common complication of lung infections caused by certain bacteria, fungi, and viruses.
“In the context of the COVID-19 pandemic, identifying factors that influence host susceptibility to and severity of pneumonia has never been more important,” the researchers wrote.
Several clinical factors and underlying conditions — such as age, chronic obstructive pulmonary disease (COPD), asthma, obesity, and diabetes — are known to influence both susceptibility to and severity of pneumonia, including that associated with COVID-19.
“However, little is known about the role of the host [genetic makeup] in the susceptibility to and severity of pneumonia,” the researchers wrote.
VUMC researchers, along with colleagues at other U.S. universities, conducted a genome-wide association study using data from the Vanderbilt University biobank (BioVU) — one of the largest single-center biobanks in the world.
Genome-wide association studies look for genetic variants that might serve as predictive markers of the presence of a trait or disease.
The team analyzed “de-identified” electronic health records covering more than 85,000 people (69,819 of European ancestry and 15,603 of African ancestry) whose genetic information was stored at BioVU.
They identified 8,889 cases of pneumonia, including 5,774 with pneumonia-associated hospitalization (in-patient status), among people of European ancestry, and 1,710 pneumonia cases, of which 1,043 were in-patients, among those of African ancestry.
In both populations, a significantly higher frequency of obesity, COPD, diabetes, asthma, and liver and kidney diseases was seen among those with a pneumonia diagnosis, in agreement with previous findings.
Study results showed that the genetic region most strongly associated with both pneumonia susceptibility and severity among those of European ancestry was located in the CF-associated CTFR gene.
In addition, CF carriers — who can pass the disease to their children but don’t have it themselves — were also more susceptible to pneumonia, but to a lesser extent than people with the full-blown disease. This is consistent with results from a previous study showing that these carriers are at higher risk of several CF-related conditions, when compared with people without CFTR mutations.
Among people of African ancestry, the mutation causing a red blood cell disorder called sickle cell disease (SCD) was significantly associated with pneumonia’s development and its severity. Disease carriers, those with only one mutated copy of the SCD-associated gene, were at increased risk for severe pneumonia.
Notably, both CF and SCD are linked to a higher risk of lung infections.
“These important genetic results indicate that individuals with CF and SCA are at heightened risk for development of and severe outcomes from pneumonia, an effect which may translate to COVID-19 outcomes,” the researchers wrote.
“Combined with systemic racism and socioeconomic factors that have been reported by others, these genetic risk differences may contribute to some of the disparities we observe in COVID-19 outcomes,” Below said.
Further research is needed “to establish whether these carriers exhibit a silent, heightened risk for poor outcomes from COVID-19 as well,” the team wrote.
When researchers excluded data from people with CF and SCD, their analysis identified two other pneumonia-associated genes: R3HCC1L in people of European ancestry, and UQCRFS1 in individuals of African ancestry.
The loss of UQCRFS1 in mice was previously shown to disrupt part of their infection-fighting immune response, while the molecular function of R3HCC1L is unclear; future studies are needed to clarify its role in pneumonia.
“Although our understanding about the genetic mechanism of pneumonia is still limited, this study identified the novel candidate genes, R3HCC1L and UQCRFS1, and offered an insight for further host genetic studies of COVID-19,” said Hung-Hsin Chen, PhD, the study’s first author and a postdoctoral fellow in Below’s lab.
Taken together, the “results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae,” the researchers concluded.
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