Welcome to this month’s Research Roundup, a recurring overview of recent studies published by researchers at BC Children’s Hospital Research Institute (BCCHR) and the University of British Columbia, and their collaborators.

BC Children's Hospital Research Institute Research Roundup

Prenatal alcohol exposure and adolescent stress increase risk of arthritis in animal model

BCCHR theme: Healthy Starts

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints that affects around one in 400 people globally and approximately one in 100 Canadians. While certain genetic variants may increase the risk for developing RA, the predominant risk factors appear to be environmental and include smoking and obesity. Research has now turned to RA risk factors that begin impacting health before an individual is born.

Dr. Joanne Weinberg, Dr. Tamara Bodnar, David Mak, Dr. Lesley Hill, Linda Ellis and Wayne Yu built upon previous knowledge that shows a link between prenatal exposure to alcohol and heightened risk of inflammatory and autoimmune disorders. Prenatal alcohol exposure can result in fetal alcohol spectrum disorder (FASD). FASD is an umbrella term referring to the broad range of physical, physiological, behavioural and cognitive effects associated with such exposure. Recent evidence suggests that the immune system and the ability to regulate inflammation may also be affected.

The research team used a rat model of prenatal alcohol exposure (PAE) to investigate the impact of PAE on the incidence, severity and course of arthritis. To model the increased exposure to stress that children with FASD often experience, adolescent rats were also exposed to chronic mild stress and compared to rats who were not exposed to the same stress.

“We found that prenatal alcohol exposure resulted in an increased incidence and severity of arthritis and impaired recovery from inflammation. And when combined with stress in adolescence, these rats showed increased inflammation and joint damage even when clinical signs of arthritis appeared to have resolved,” says Dr. Weinberg.

Together, these findings indicate a significant impact of early environmental exposure, such as prenatal exposure to alcohol, on the immune system.

“There is a scarcity of clinical data regarding the link between FASD and autoimmune disorders such as rheumatoid arthritis,” adds Dr. Weinberg. “For this reason, further studies are needed to explore the connection between FASD and the later development of immune and autoimmune disorders in humans.”

Read more in “Modulatory Role of Prenatal Alcohol Exposure and Adolescent Stress on the Response to Arthritis Challenge in Adult Female Rats,” EBioMedicine.

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Uncovering genetic factors that influence cardiac safety of ondansetron

BCCHR themes: Evidence to Innovation, Healthy Starts and Childhood Diseases

Ondansetron is a medication commonly prescribed to reduce nausea and vomiting. In pediatrics, ondansetron is given to children who have just had surgery and to those receiving chemotherapy as part of cancer treatment. The medication is also sometimes prescribed during pregnancy when first-line treatments do not work to reduce nausea and vomiting.

Ondansetron has been associated with a cardiac effect called QT prolongation, which refers to an extended interval between heartbeats. QT prolongation may increase the risk of abnormal heart rhythms and even sudden cardiac arrest.

Dr. Bruce Carleton, Dr. Britt Drögemöller, Dr. Galen Wright, Jessica Trueman, Fudan Miao, Michelle Higginson, Gabriella Groeneweg, Dr. Laura Magee, Dr. Simon Whyte, Nicholas West, Sonia Brodie, Dr. Rod Rassekh, Dr. Shubhayan Sanatani, Dr. Colin Ross and their collaborators performed the first known investigation into the genetic factors that influence the cardiac safety of ondansetron. The team enrolled 257 patients from three different patient groups: pediatric day surgery patients, pediatric oncology patients, and pregnant women receiving ondansetron before C-section.

Unsafe QT prolongation was observed in three patients (one from each group) and longer QT intervals were observed in roughly a quarter of patients. In addition to using electrocardiograms to measure QT intervals in the patients, the team also conducted a genome-wide association study (GWAS) to look for genetic variants associated with these cardiac effects of ondansetron. They identified six genes associated with ondansetron-induced QT prolongation, including two variants that protected patients from QT prolongation.

“Our findings provide valuable insight regarding the genetic factors that place some individuals at higher and lower risk for QT prolongation while taking ondansetron,” says Dr. Carleton. “This is the first step towards the use of pharmacogenomic information when prescribing this medication.”

Pharmacogenomics refers to the study of how a patient’s genes affect how they respond to particular medications.

“In the future, health-care professionals will be equipped to consider the genetic susceptibilities of patients before prescribing this common antiemetic medication,” adds Dr. Carleton. “An individual’s pharmacogenomic profile can indicate whether they are safely able to take a particular medication and whether they require a higher or lower dose.”

Read more in “A Pharmacogenomic Investigation of the Cardiac Safety Profile of Ondansetron in Children and Pregnant Women,” Biomedicine & Pharmacotherapy.

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Most patients have no regrets when it comes to learning about ‘surprise’ genetic disease susceptibility

BCCHR themes: Childhood Diseases and Evidence to Innovation

Genome-wide sequencing (GWS) is a type of genetic testing where the entire genome is analyzed for the purpose of diagnosing genetic conditions. GWS has become increasingly common in clinical practice, underscoring the importance of knowing whether patients experience harm when learning about their genetic disease susceptibilities. In the field of genetic counselling, harmful or disease-causing genetic variants detected unintentionally during testing for a different condition are called incidental findings (IFs).

There has been much debate in recent years over which IFs should be routinely reported back to patients and families. However, recent research indicates that the majority of patients — roughly nine in 10 — want to know about IFs.

Shelin Adam, Faith Cheung, Patricia Birch, Dr. Jan Friedman, Dr. Alison Elliott and their collaborators gauged the impact on patients and families after receiving IF news. Did they experience harm and what was the long-term impact?

The team interviewed parents who received IFs as part of the CAUSES translational research study at BC Children’s Hospital and BC Women’s Hospital + Health Centre. Out of 901 parents who agreed to learn about IFs, only 21 parents had IFs. Twelve out of these 21 parents agreed to participate in the study led by Ms. Adam and were interviewed an average of two years after receiving news of their IFs.

“We learned that patients are really motivated to learn about their IFs if they feel that the advantages to knowing outweigh the potential risks. They want to know how to prevent the disease in question or how they might change lifestyle behaviours to reduce their chances of illness. Also, many are strongly motivated to learn about IFs if they have a child with a suspected genetic condition, as they really want all the information they can get to help their child,” says Ms. Adam.

“In our study, we wanted to know about the longer-term impacts of IF knowledge, and all respondents said that receiving information about the IF had little negative impact on their lives,” she adds. “Participants felt that having knowledge of their IF was useful or would be useful in the future.”

Read more in “The Long-Term Impact of Receiving Incidental Findings on Parents Undergoing Genome-Wide Sequencing,” Journal of Genetic Counseling.


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