Liam Brunham

Associate Professor

Research Classification

Research Interests

Lipids
Genetics
Pharmacogenomics
Cardiovascular diseases

Relevant Thesis-Based Degree Programs

Research Options

I am available and interested in collaborations (e.g. clusters, grants).
I am interested in and conduct interdisciplinary research.
I am interested in working with undergraduate students on research projects.
 
 

Research Methodology

Next generation sequencing
Genome editing
Induced pluripotent stem cells
Genome wide association studies
clinical trials

Recruitment

Master's students
Doctoral students
Postdoctoral Fellows
Any time / year round

1. SAVE BC (www.savebc.ca) is a provincial study of families with extremely premature cardiovascular disease, aimed at identifying molecular causes of this condition and reducing the burden of premature cardiovascular disease. 2. Pharmacogenomics of adverse drug reactions. We are using human stem cells to study the pharmacogenetic mechanisms of specific adverse drug reactions. This work will lead to new approaches to identify patients at risk of suffering from adverse drug reactions, and the development of safer, more effective medications. 3. Inherited dyslipidemias. We have one of the largest and most established registries in Canada of patients with Familial Hypercholesterolemia, a common cause of premature CVD which is under-recognized and under-treated. We are investigating the use of genetic testing to improve the diagnosis of patients with this condition, and understand the determinants of cardiovascular disease risk in these patients.

I support public scholarship, e.g. through the Public Scholars Initiative, and am available to supervise students and Postdocs interested in collaborating with external partners as part of their research.
I support experiential learning experiences, such as internships and work placements, for my graduate students and Postdocs.
I am open to hosting Visiting International Research Students (non-degree, up to 12 months).
I am interested in hiring Co-op students for research placements.

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ADVICE AND INSIGHTS FROM UBC FACULTY ON REACHING OUT TO SUPERVISORS

These videos contain some general advice from faculty across UBC on finding and reaching out to a potential thesis supervisor.

Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Plasma lipoproteins : genetic influences and relevance to atherosclerotic and infectious diseases (2023)

Plasma lipoproteins, such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein(a) are highly heritable traits and important biomarkers for atherosclerotic cardiovascular disease (ASCVD). LDL and lipoprotein(a) are atherogenic plasma lipoproteins that are often both elevated among individuals with familial hypercholesterolemia; a common, autosomal co-dominant disorder characterized by pathogenic DNA variants in the LDLR, APOB, and PCSK9 genes. These pathogenic variants impair the removal of LDL from the blood and lead to severe hypercholesterolemia and increased risk of ASCVD. Despite the ability to identify individuals with a genetic cause for familial hypercholesterolemia or elevated lipoprotein(a), one of the most challenging aspects in the clinical management of this patient population is the remarkable diversity of ASCVD risk.Alternatively, HDL has been thought to protect against atherosclerosis because low levels of HDL are strongly associated with increased risk of ASCVD. Several recent clinical trials have unsuccessfully attempted to raise HDL cholesterol to reduce the risk of ASCVD. These results have left unanswered questions about the primary function(s) of HDL. Plasma lipoproteins undergo extensive changes in structure, function, and metabolism during severe infections such as sepsis. However, the implications and causality of these changes to clinical outcomes is poorly understood.The central objective was to explore the contribution of genetic variation in plasma lipoprotein traits and metabolism on lipid disorders such as familial hypercholesterolemia, elevated lipoprotein(a), and serious infections such as sepsis. Here, we used genetic epidemiology and mouse models of disease to assess how common and rare germline genetic variation affects the risk of atherosclerotic cardiovascular diseases and infectious diseases. Specifically, 1) can background genetic variation related to LDL and lipoprotein(a) modify the risk of ASCVD for individuals with familial hypercholesterolemia? and 2) are associations between HDL and risk of infectious disease causal? Several broad conclusions can be made. First, background polygenic factors influencing LDL-C and lipoprotein(a) levels modify the penetrance and expressivity of familial hypercholesterolemia. Second, the primordial function of HDL may be related to immunoregulation and resolution of infection. Third, cholesteryl ester protein is an important regulator of HDL levels during sepsis and may be a therapeutic target.

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Prediction and mechanisms of doxorubicin-induced cardiotoxicity : role of RARG and cardioprotective effects of SGLT2 inhibitor (2023)

Doxorubicin is a commonly used chemotherapy drug that treats both adult and childhood cancers, but its clinical usefulness is limited by doxorubicin-induced cardiotoxicity (DIC). The incidence of DIC increases up to 65% at cumulative doses of 550 mg/m², which leads to irreversible heart failure and death. Since some patients suffer from DIC even at low doses, genetic differences may account for some of the inter-individual variability in risk for DIC and several associated genetic variants have been identified. Among these variants, RARG-S427L is one of the top variants that shows strong evidence of association with DIC. Sodium-glucose transport protein 2 inhibitors (SGLT2i) are effective glucose-lowering medications that are indicated for type 2 diabetes mellitus treatment. SGLT2i have also been demonstrated to be cardioprotective for heart failure. We still lack ways to predict and prevent DIC. The goal of this dissertation is to investigate the impacts and mechanism of RARG-S427L variant in DIC and the potential cardioprotective effects of SGLT2i against DIC. I hypothesized that RARG-S427L increases the risk of DIC and the SGLT2i (empagliflozin) protects against DIC. To conduct this work, I developed a patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) model of DIC and used this to show that RARG-S427L increases susceptibility to DIC by orchestrating a DNA repair response to doxorubicin. Furthermore, co-treatment with empagliflozin reduced doxorubicin-induced cell death and up-regulated fatty acid metabolism-related gene expression. In summary, our findings reveal the roles of RARG-S427L in transcriptional response to doxorubicin in cardiomyocytes and identify empagliflozin as a potential cardioprotective agent against DIC, with implications for personalized risk prediction and the potential usage of empagliflozin to prevent this adverse drug reaction.

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Modelling adverse drug reactions using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) (2021)

Adverse drug reactions (ADRs) constitute the fourth leading cause of death and their incidence is steadily increasing. Cardiovascular toxicity is one of the most common and serious ADR and is the leading cause of drug discontinuation. The overarching goal of this thesis is to investigate cardiac ADRs using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs). Doxorubicin is a chemotherapy drug administered to adult and pediatric patients for the treatment of hematological and solid tumors, however, it can cause doxorubicin induced cardiotoxicity (DIC). We generated induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients who received doxorubicin as part of their chemotherapy regimen. iPSC-CMs from individuals who developed DIC displayed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from patients who did not experience DIC. Several variants associated with DIC have been identified, with RARG –S427L having the strongest genetic evidence. iPSC-CMs together with genome editing, provide a powerful platform to establish causal relationships between genetic variants and ADRs. We used CRISPR/Cas9 to investigate the functional impact of RARG-S427L on DIC in isogenic patient derived iPSC-CMs that differed only at the RARG locus. Genetic correction of RARG-S427L decreased susceptibility to in vitro DIC, whereas introduction of RARG-S427L had the opposite effect. We also used this platform to identify novel cardioprotectants that can be used clinically to prevent DIC. Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, is an FDA-approved medication for the treatment of diabetes that shows cardiovascular benefits. iPSC-CMs treated with empagliflozin exhibited reduced doxorubicin induced cell death. Finally, we showed that enriched cardiomyocyte subtype populations are necessary for accurate drug screening and disease modelling. Ibrutinib is an anticancer drug indicated for the treatment of B cell malignancies; however, it can cause atrial fibrillation. We used atrial and ventricular hPSC-CMs to study ibrutinib induced atrial fibrillation. Ibrutinib had an arrhythmogenic impact on hPSC atrial derived cardiomyocytes, while ventricular hPSC remained unaffected. Collectively, our findings demonstrate that hPSC-CMs represent a powerful platform for disease modelling and drug screening that is amenable to personalized risk prediction for the prevention of adverse drug reactions.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Indigenous cardiovascular health: assessing disease, risk factors, and patient care (2024)

Background: Indigenous Peoples are extremely diverse and have unique cultural and social histories that have allowed them to remain resilient through decades of colonialism aimed to disrupt the health of their communities. Chronic diseases, including cancer, diabetes, and atherosclerotic cardiovascular disease (ASCVD) are leading causes of morbidity and mortality and disproportionately impacts Indigenous populations. In high income countries, such as Canada, Indigenous populations experience ASCVD rates 1.5 to 2.5 times higher than their non-Indigenous counterparts. There are several factors which contribute to this disproportionate burden of ASCVD, including systematic racism and discrimination in healthcare, however, social determinants of health, such as these, are often overlooked when designing and implementing healthcare strategies in the current western-based medical system. Methods: To generate background knowledge, we conducted a comprehensive narrative review examining existing studies and grey literature on the prevalence of ASCVD in Indigenous populations in Canada and discuss recommendations for future addressment strategies (Chapter 1). To understand major risk factors for ASCVD, we conducted a systematic review and meta-analysis estimating the prevalence of hypercholesterolemia in Indigenous populations (Chapter 2). Addressing the need to understand how Indigenous patients view equitable cardiovascular care, we conducted a prospective observational study assessing the cardiovascular care of Indigenous patients with premature ASCVD (Chapter 3). Results: Our findings reveal significantly higher rates of ASCVD in Indigenous populations compared to non-Indigenous populations. While hypercholesterolemia and familial hypercholesterolemia, significant risk factors for ASCVD, were found to be inadequately studied in Indigenous populations, we estimated the pooled-prevalence of hypercholesterolemia to be 28.9%, demonstrating it is extremely common in Indigenous populations. To address ASCVD, Indigenous populations should be provided access to evidence-based cardiovascular care which we found increases medication uptake and significantly improves lipid profiles, decreasing risk of recurrent cardiovascular events for Indigenous patients. Conclusion: Indigenous populations are significantly impacted by ASCVD and major risk factors, including hypercholesterolemia. We recommend the establishment of collaborative alliances with Indigenous communities to augment the accessibility of screening and testing services, thereby enhancing Indigenous Peoples' awareness of ASCVD, and major associated risk factors, and affording them the autonomy to participate in screening initiatives at their discretion.

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Publications

 
 

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