Laura Arbour receives funding to study potentially fatal genetic condition in Northern BC First Nations communities

Dr. Laura Arbour, a UBC Professor of Medical Genetics and an Affiliate Professor in UVic’s Division of Medical Sciences, was recently awarded two operating grants by the Canadian Institute of Health Research (CIHR).

laThe grants will support Dr. Arbour’s Community Genetics Research Program, which studies how a rare genetic condition, called Long QT Syndrome, disproportionally affects First Nations populations in Northern BC.

“Our work has focused for more than a decade on genetic susceptibility factors and health in Indigenous populations,” said Dr. Arbour. “The two CIHR-funded studies will be carried out in partnership with the Gitxsan First Nations of Northern BC, who have a high rate of Long QT Syndrome – a hereditary heart condition that, if left unrecognized, could be fatal.”

In the inherited version of Long QT Syndrome, also known as LQTS, a mutation will occur in one of several genes that control heart rhythm. Normally, a person’s heart will beat at a regulated pace, which increases or decreases depending on the person’s activity level. The heart’s electrical activity can be captured by an electrocardiogram (EKG); the P, Q, R, S, and T waves reflect the pattern of electrical peaks that influence the contraction and relaxation of the heart’s chambers. The QT interval, which specifically maps the contraction-and-relaxation phase of the heart’s ventricles, should measure as about one-third of each heartbeat. If this interval is too long (LQTS), there is a risk the heart rhythm will become abnormal, and possibly chaotic. This can lead to fainting, seizures, and even sudden death.

Long QT Syndrome affects roughly 1 in 2000 people worldwide. But in Northwest BC, some First Nations groups have mutations in a gene called KCNQ1, passed down through many generations, resulting in at least 1 in 125 people having a genetic predisposition to LQTS.

Study 1: Long QT syndrome in Northern British Columbia: Gene-gene interaction, life course differences, and implications for safe management (four-year funding).

In this newly funded study, Dr. Arbour will focus on children and young women with Long QT Syndrome caused by a mutation in the KCNQ1 gene. Scientists recently discovered that, besides the heart, KCNQ1 also operates in the pancreas. The mutation in KCNQ1 that results in LQTS may not only disturb the heart’s rhythm, but may also increase insulin secretion in the pancreas, resulting in low blood sugar.

But the situation is made more complicated, said Dr. Arbour, due to another gene, called CPT1a, which affects how fat is used for energy during fasting. 50% of First Nation Peoples in Northern BC carry one copy of a CPT1a gene variant (P479L) common in Northern Indigenous populations, and 25% carry two copies. Only a small number of those with two copies of the CPT1a gene change are expected to develop low blood sugar caused by the impaired fat metabolism. However, because the CPT1a gene variant is so common in Northern BC, Dr. Arbour suspects that 50% of those carrying the KCNQ1 mutation will also carry at least one copy of the CPT1a variant; those with both would be at higher risk for low blood sugar, because of the effect both genes have on blood sugar. Four children, each with a combination of CPT1a and KCNQ1 variants, have presented with symptomatic low blood sugar to date.

Dr. Arbour’s research team of cardiologists, pediatricians, laboratory scientists, and genetic counselors will focus on understanding the circumstances of risk and determine the best treatment options for those affected.

Study 2: Understanding the population, individual, and cellular effects of a novel ANK2 mutation associated with Long QT syndrome and structural heart disease in a First Nations community of Northern British Columbia (bridge funding for one year).

The second CIHR-funded study will pair Dr. Laura Arbour with fellow faculty member Dr. Leigh Anne Swayne, an Associate Professor of Neuroscience in UVic’s Division of Medical Sciences.

Drs. Arbour and Swayne recently found out that two large First Nations families in Northern BC have a unique strain of Long QT Syndrome, called LQTS4. It was caused, not by a mutation in KCNQ1, the common founder gene, but by a mutation in another gene called ANK2. This mutation not only bears responsibility for LQTS4, which has a host of atypical issues not found in classic LQTS, but may also contribute to other health problems, such as structural heart disease, seizures, and possibly even cerebral aneurysms.

As a result, Drs. Arbour and Swayne want to discover precisely what roles that ANK2 play in the heart and brain; how those roles lead to the LQTS4; and other health problems to which this gene could be linked. To this end, Drs. Arbour and Swayne will study cellular models of the heart and brain. This work capitalizes on Swayne’s expertise on protein biochemistry and cellular biology, and it will help to further her lab's long-term research goal to increase the understanding of regulation and function of proteins in the context of health and disease. 

The successful collaboration between Drs. Arbour and Swayne forges an important new interdisciplinary research program whose outcomes will produce better ways to diagnose and treat these diseases, as well as improve patient care.