CF Mutation Carriers Have Increased Risk for Gastrointestinal Problems, Large-scale Study Finds

Alice Melão, MSc avatar

by Alice Melão, MSc |

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carriers of CF-related mutations

People who carry certain genetic mutations associated with cystic fibrosis, (CF) but who do not have the disease, are at risk for some gastrointestinal problems similar to those reported by CF patients, a large-scale study shows.

This finding helps better understand the impact of genetic mutations linked to CF, as well as to support the development of new strategies to improve the health of those who are carriers without the disease.

The study findings were discussed recently at the American Society of Human Genetics (ASHG) 2019 Annual Meeting in Houston, Texas, during an oral presentation titled “Defining the phenotypic signature of CFTR mutation carriers in the UK Biobank.”

CF is an inherited disorder that is mostly recognized for its respiratory symptoms, but it also can affect other organs, including those of the digestive system.

Several genetic mutations in the CF transmembrane conductance regulator (CFTR) gene have been identified and linked to the disease. Genetic variants of other genes commonly known as modifier genes, such as the SLC9A3 gene,  also have been identified and recognized as contributing to disease severity and development of secondary health problems.

CF is known to be a recessive genetic disease, meaning that it is necessary to have both copies of the CFTR gene — one inherited from the mother and the other from the father — affected by genetic mutations. So, a child may have CF while the parents may just be carriers of the genetic mutations without experiencing clinical symptoms of the disease.

Many advances have been made in understanding CF and its underlying mechanism in the past decades. Still, it remains unclear if people who carry CF-related mutations also may experience some health problems due to their carrier status.

“Although many individuals are learning of their CFTR carrier status through family planning or the use of personal genomics companies, researchers have not yet thoroughly investigated whether a phenotype for cystic fibrosis carriers exists,” Lisa Strug, PhD, said in a press release. Strug is associate director of The Centre for Applied Genomics at The Hospital for Sick Children in Toronto, Canada, and senior author of the study.

To shed light on this matter, researchers reviewed clinical and genetic information of approximately 500,000 individuals registered at the U.K. Biobank.

The team identified 8,700 individuals who were carriers of at least one copy of the most common CF-causing variant in CFTR, referred to as F508del mutation.

Results showed an “association between carrier status and several digestive phenotypes, including obstruction of bile duct” researchers wrote. CFTR mutation carriers had a 2.09-fold increased chance of having obstruction of bile duct compared to non-carriers, which is a common complication experienced by CF patients.

Being carriers of F508del as well as of altered SLC9A3 gene — a CF gene modifier linked to intestinal obstruction — was linked to esophagitis (inflammation of the esophagus), gastroesophageal reflux disease (GERD, aka acid reflux), and related conditions.

These data suggested that CF modifier genes also cancontribute to gastrointestinal symptoms among individuals without CF.

“We found that carriers were twice as likely as non-carriers to experience bile duct obstruction,” said Yu-Chung Lin, a graduate student at the University of Toronto and who presented the data at ASHG.

“While it is important to note that being a carrier doesn’t predict symptoms for any given individual, the association study shows that there may be phenotypic risks to having even one copy of the cystic fibrosis variant. It’s important to consider the clinical impact of this information carefully,” Lin said.

The research team plans to continue exploring potential associations between CF carrier status and clinical manifestation of symptoms, such as cough and lung function problems. They also will further assess the impact of CF modifier genes on symptoms experienced by carriers.

“Improved understanding of elevated burden of disease could be integrated with genetic testing to achieve better health for the large numbers of CF carriers in populations,” the team concluded.