Overview

In recent years, opioids have been linked to negative consequences for both maternal and child health. For example, codeine has been responsible for death in both breastfed infants and children after surgery. This has led to warnings issued by several regulatory agencies around the world, including Health Canada, and a subsequent reduction in the use of codeine for pain relief in women and children. However, responses to alternative pain medications, such as morphine, also vary widely between individuals, limiting the ability to choose medications that optimize pain relief while avoiding harm.

Importantly, safe and effective pain management is influenced by individual genetic differences that dictate both how we feel pain and how we respond to specific pain medications. Using pharmacogenomics, the study of how genetic variability contributes to individual drug responses, we are identifying genetic factors that can help predict an individual’s need for, and subsequent response to, specific pain medications. As part of the multi-disciplinary Canadian Pharmacogenomics Network for Drug Safety (CPNDS), we are working closely with clinicians, scientists, and patients across the country to develop a pipeline from genetic discoveries to predictive genetic testing to help select the safest and most effective medications for women and children based on their unique genetic signatures.

Our work will allow for more individualized risk-benefit decisions for pain management in women and children, while also contributing to the discovery of novel components of pain response pathways that could pave the way for novel pain management strategies with increased safety and effectiveness.

Publications

Pharmacogenetic testing to guide therapeutic decision-making and improve outcomes for children undergoing anthracycline-based chemotherapy
Basic and Clinical Pharmacology and Toxicology
Loucks, C.M. and Yan, K. and Tanoshima, R. and Ross, C.J.D. and Rassekh, S.R. and Carleton, B.C.
DOI: 10.1111/bcpt.13593
2021

Pharmacogenomic testing: Enhancing personalized medication use for patients
Canadian Family Physician
Loucks, C.M. and Groeneweg, G. and Roy, C. and Lee, D.K. and Rieder, M.J. and Lebel, D. and Ito, S. and Ross, C.J. and Carleton, B.C.
2020

Les tests pharmacogénomiques: Améliorer le recours personnalisé aux médicaments pour les patients
Canadian family physician Medecin de famille canadien
Loucks, C.M. and Groeneweg, G. and Roy, C. and Lee, D.K. and Rieder, M.J. and Lebel, D. and Ito, S. and Ross, C.J. and Carleton, B.C.
2020

CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines
Breast Cancer Research and Treatment
Dr{\"o}gem{\"o}ller, B.I. and Wright, G.E.B. and Shih, J. and Monzon, J.G. and Gelmon, K.A. and Ross, C.J.D. and Amstutz, U. and Carleton, B.C. and Chang, W.C. and Connolly, M.B. and Dionne, F. and Groeneweg, G. and Loucks, C.M. and MacLeod, S.M. and Pritchard, S. and Rassekh, S.R. and Sanatani, S. and Tanoshima, R. and Virani, S.A. and Monzon, J.G. and Bhavsar, A.P. and Rieder, M.J. and Shear, N.H. and Liu, G. and Khayat, P. and Bernstein, D. and Lesko, L.J. and Aminkeng, F.
DOI: 10.1007/s10549-018-5027-0
2019

Efhc1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling
eLife
Loucks, C.M. and Park, K. and Walker, D.S. and McEwan, A.H. and Timbers, T.A. and Ardiel, E.L. and Grundy, L.J. and Li, C. and Johnson, J.-L. and Kennedy, J. and Blacque, O.E. and Schafer, W. and Rankin, C.H. and Leroux, M.R.
DOI: 10.7554/eLife.37271
2019

PACRG, a protein linked to ciliary motility, mediates cellular signaling
Molecular Biology of the Cell
Loucks, C.M. and Bialas, N.J. and Dekkers, M.P.J. and Walker, D.S. and Grundy, L.J. and Li, C. and Inglis, P.N. and Kida, K. and Schafer, W.R. and Blacque, O.E. and Jansen, G. and Leroux, M.R.
DOI: 10.1091/mbc.E15-07-0490
2016

Matching Two Independent Cohorts Validates DPH1 as a Gene Responsible for Autosomal Recessive Intellectual Disability with Short Stature, Craniofacial, and Ectodermal Anomalies
Human Mutation
Loucks, C.M. and Parboosingh, J.S. and Shaheen, R. and Bernier, F.P. and Mcleod, D.R. and Seidahmed, M.Z. and Puffenberger, E.G. and Ober, C. and Hegele, R.A. and Boycott, K.M. and Alkuraya, F.S. and Innes, A.M.
DOI: 10.1002/humu.22843
2015

Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans
American Journal of Human Genetics
Shaheen, R. and Shamseldin, H.E. and Loucks, C.M. and Seidahmed, M.Z. and Ansari, S. and Ibrahim Khalil, M. and Al-Yacoub, N. and Davis, E.E. and Mola, N.A. and Szymanska, K. and Herridge, W. and Chudley, A.E. and Chodirker, B.N. and Schwartzentruber, J. and Majewski, J. and Katsanis, N. and Poizat, C. and Johnson, C.A. and Parboosingh, J. and Boycott, K.M. and Innes, A.M. and Alkuraya, F.S.
DOI: 10.1016/j.ajhg.2013.11.010
2014

Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability
American Journal of Human Genetics
B{\"o}gershausen, N. and Shahrzad, N. and Chong, J.X. and Von Kleist-Retzow, J.-C. and Stanga, D. and Li, Y. and Bernier, F.P. and Loucks, C.M. and Wirth, R. and Puffenberger, E.G. and Hegele, R.A. and Schreml, J. and Lapointe, G. and Keupp, K. and Brett, C.L. and Anderson, R. and Hahn, A. and Innes, A.M. and Suchowersky, O. and Mets, M.B. and N{\"u}rnberg, G. and McLeod, D.R. and Thiele, H. and Waggoner, D. and Altm{\"u}ller, J. and Boycott, K.M. and Schoser, B. and N{\"u}rnberg, P. and Ober, C. and Heller, R. and Parboosingh, J.S. and Wollnik, B. and Sacher, M. and Lamont, R.E.
DOI: 10.1016/j.ajhg.2013.05.028
2013

Congenital stationary night blindness: Mutation update and clinical variability
Advances in Experimental Medicine and Biology
Lodha, N. and Loucks, C.M. and Beaulieu, C. and Parboosingh, J.S. and Bech-Hansen, N.T.
DOI: 10.1007/978-1-4614-0631-0_48
2012

A shared founder mutation underlies restrictive dermopathy in Old Colony (Dutch-German) Mennonite and Hutterite patients in North America
American Journal of Medical Genetics, Part A
Loucks, C. and Parboosingh, J.S. and Chong, J.X. and Ober, C. and Siu, V.M. and Hegele, R.A. and Rupar, C.A. and Mcleod, D.R. and Pinto, A. and Chudley, A.E. and Innes, A.M.
DOI: 10.1002/ajmg.a.35302
2012

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone
American Journal of Human Genetics
Huang, L. and Szymanska, K. and Jensen, V.L. and Janecke, A.R. and Innes, A.M. and Davis, E.E. and Frosk, P. and Li, C. and Willer, J.R. and Chodirker, B.N. and Greenberg, C.R. and McLeod, D.R. and Bernier, F.P. and Chudley, A.E. and M{\"u}ller, T. and Shboul, M. and Logan, C.V. and Loucks, C.M. and Beaulieu, C.L. and Bowie, R.V. and Bell, S.M. and Adkins, J. and Zuniga, F.I. and Ross, K.D. and Wang, J. and Ban, M.R. and Becker, C. and N{\"u}rnberg, P. and Douglas, S. and Craft, C.M. and Akimenko, M.-A. and Hegele, R.A. and Ober, C. and Utermann, G. and Bolz, H.J. and Bulman, D.E. and Katsanis, N. and Blacque, O.E. and Doherty, D. and Parboosingh, J.S. and Leroux, M.R. and Johnson, C.A. and Boycott, K.M.
DOI: 10.1016/j.ajhg.2011.11.005
2011

Research

Current Projects
Oral morphine is commonly used for pain relief in children, yet individual responses are often difficult to predict. Specifically, some children will experience inadequate pain relief while others may be at risk of suffering life-threatening consequences. Individual genetic differences have been found to contribute to the likelihood that morphine will be both safe and effective for a particular child. However, it remains uncertain how identified genetic factors could be used to improve pain management due to limited investigations or inconsistent findings. We are using both pharmacogenomics, the study of how genetic variability contributes to individual drug responses, and pharmacokinetics, the study of how drugs are processed inside the body, to identify individual characteristics that reliably help predict a child’s response to morphine prior to treatment. To do this, we will recruit childhood cancer patients treated with oral morphine for pain relief, collect detailed information on how morphine is processed in different children, and generate genetic data to develop a pharmacokinetic-pharmacogenomic model to help explain, and eventually predict, variable responses. This work will pave the way to better dosing strategies and allow patients and clinicians to appropriately balance the benefits and risks associated with morphine-based pain management.

Pain as a result of specific anti-cancer drugs is commonly encountered in both children and adults. However, while some patients suffer pain as a result of treatment, other similarly-treated patients are spared from this pain. For example, methotrexate is effectively used to treat several cancers, yet some patients develop mucositis, a painful inflammation and ulceration of mucosal linings found at various locations throughout the body (e.g., the eyes, ears, mouth, digestive tract and vagina). Mucositis is particularly distressing for children, and in severe cases, it is life-threatening due to increased susceptibility to infection or the inability to proceed with anti-cancer drug treatment. Although 28 genetic variants have been significantly associated with methotrexate-induced mucositis in at least one study, their predictive value remains uncertain due to limited replication attempts or inconsistency between studies. We have recruited methotrexate-treated children from across Canada, collected detailed information on treatments received (and symptoms suffered), and generated comprehensive genetic data to identify genetic factors that can predict who is most likely to develop painful mucositis. Ultimately, identified genetic factors will be used to design predictive genetic tests that will guide pain management strategies to limit, or even prevent, unnecessary pain encountered during cancer treatment.

Grants

BC Children’s Hospital Research Institute Evidence to Innovation (E2i) Research Theme Seed Grant: “Development of a pharmacokinetic-pharmacogenomic model to enhance morphine-based pain management in children” (2021)

Honours & Awards

Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Cross-Disciplinary Training (DSECT) Award (Stream 2, advanced skill training) (2020-2021)

Peter Dresel Trainee Presentation Award at the CSPT (Canadian Society of Pharmacology and Therapeutics) 2020 Virtual Conference (2020)

Canadian Institutes of Health Research (CIHR) Fellowship (2020-2021)

BC Children’s Hospital Research Institute Bertram Hoffmeister Postdoctoral Fellowship (2018-2019)

Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Cross-Disciplinary Training (DSECT) Award (Stream 1, foundational skill training) (2018-2019)