Scientists Discover a Genetic Combination that may Worsen Pulmonary Disease in Paediatric CF Patients

Scientists at The Hospital for Sick Children (SickKids), the University of British Columbia (UBC), the University of Toronto (UofT) and Université de Montréal (UdeM) have identified key genetic factors influencing the severity of lung disease in paediatric cystic fibrosis (CF) patients. Their research is reported this month in The Journal of Clinical Investigation.

According to the research, paediatric patients with cystic fibrosis (CF) who carry a gene variant that produces a low amount of MBL2 or mannose binding lectin 2, and who carry a high producing variant of the TGFB1gene or transforming growth factor beta 1 gene, have a greater risk of acquiring the bacterial infection that may accelerate the decline of their lung function.

Virtually all CF patients are prone to acquiring the Pseudomonas aeruginosa bacteria, which leads to the development of lung diseases that progress with age. Because MBL2 plays a key role in the first defense against bacterial infection, the bacteria tend to invade lungs at an earlier age in those who are MBL2 deficient and may lead to a chronic infection and resistance to antibiotics much sooner than in those with normal levels of the protein in their blood. The mechanisms by which elevated levels of TGFB1 lead to more severe lung disease are yet to be investigated.

“The study shows that those exhibiting this genetic combination may be at a higher risk of acquiring this infection at a younger age - on average nearly five years earlier than those with gene variants that produce normal MBL2 and TGFB1 levels - most likely leading to a faster rate of decline of pulmonary function,” explains Dr. Julian Zielenski, an Associate Scientist in the Genetics & Genome Biology program at SickKids and a lead author of the study.

“Patients experience a vicious cycle of infection and inflammation that destroys lung tissue, inhibits lung function, and erodes quality of life. Since pulmonary disease is also the leading cause of mortality among CF patients, examining the genetics that help invite, sustain, or advance infection is critical,” Zielenski.

While we are excited by the discovery and its future implications for prognosis and therapeutics, the findings cannot be used yet to accurately or consistently predict the outcome in individual patients who exhibit this adverse genetic combination,” cautions Zielenski. “There are many other CF modifier genes which may positively or negatively affect CF disease. After a sufficient number are identified, scientists could develop a genetic test to reliably predict the severity of lung disease at the individual level, or begin clinical trials to evaluate the benefit of supplementing these patients with functional MBL2 protein.”

The results for this discovery were derived from a genetic association study that compared the MBL2 and TGFB1genotypes of 1,019 CF children, recruited from Canada's 37 CF clinics.