Scientists discover a genetic combination that may worsen pulmonary disease in paediatric CF patients;

    Finding could pave the way for future clinical trials and genetic tests

    TORONTO, Feb. 21 /CNW/ - 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."
    "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. The study was conducted under the
auspices of the Canadian Consortium for CF Genetic Studies, consisting of
investigators and clinical collaborators who established a Canadian CF
population resource of clinical data and biological material. The Consortium
promotes scientific discovery toward a better understanding of CF and related
    Researchers from four Canadian Institutions were involved in the study,
whose other key authors include Postdoctoral Fellow in the Genetics & Genome
Biology program Dr. Ruslan Dorfman (first author), Senior Scientist in the
Physiology & Experimental Medicine program Dr. Peter Durie (co-leader of the
Canadian CF Modifier Study), and Senior Scientist in the Child Health
Evaluative Sciences program Dr. Mary Corey, all at SickKids, as well as UBC
Scientists Drs. Peter Pare and Andrew Sandford, Dr. Lap-Chee Tsui at
University of Hong Kong, Dr. Lei Sun, a Biostatistician at UofT, and Dr. Yves
Berthiaume, a Clinical Scientist at UdeM. Funding from Genome Canada, with
co-funding from the Canadian Cystic Fibrosis Foundation, the Ontario Research
Fund - Research Excellence Program, the Lloyd Carr-Harris Foundation, and
SickKids Foundation supported the research.
    Moving forward, the Canadian Consortium for CF Genetic Studies will
search for other CF modifiers using a new approach called a Genome-Wide
Association Study. The team at SickKids has partnered with US researchers at
the University of North Carolina, Case Western Reserve University, and Johns
Hopkins University to study over 5,000 patients, examining 550,000 genetic
markers representing the entire human genome. The study is supported by a
large grant from the US Cystic Fibrosis Foundation, as well as the US National
Institutes of Health, Genome Canada and its co-funders. Using this approach,
the team hopes to isolate additional undiscovered genetic modifiers that are
not typically associated with CF.

    The Hospital for Sick Children (SickKids), affiliated with the University
of Toronto, is Canada's most research-intensive hospital and the largest
centre dedicated to improving children's health in the country. As innovators
in child health, SickKids improves the health of children by integrating care,
research and teaching. Our mission is to provide the best in complex and
specialized care by creating scientific and clinical advancements, sharing our
knowledge and expertise and championing the development of an accessible,
comprehensive and sustainable child health system. For more information,
please visit SickKids is committed to healthier children for
a better world.

For further information:

For further information: Janice Nicholson, The Hospital for Sick
Children, (416) 813-6684,

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