Revolutionizing Sepsis Treatment: How Mendelian Randomization Can Help Identify Causal Relationships

November 21, 2023

Sepsis is the life-threatening response to an infection leading to organ dysfunction and death and affects millions of people each year worldwide. There is significant variation in how sepsis progresses in different individuals, and how individuals respond to existing treatments for sepsis. It is currently unknown how different genes, proteins, and lipids (i.e., fats) interact to cause sepsis; however, this knowledge could help inform more effective treatments against sepsis.  Mendelian randomization is a technique that can be used to determine whether certain traits, such as the amount of certain protein or lipid in the blood, cause a particular clinical outcome, such as sepsis. Recent research published in Intensive Care Medicine indicates that this could hold the key to discovering novel therapies against sepsis.

Mendelian randomization is a simple concept but somewhat complex operationally. However, the potential rewards are immense because this technique moves the evidence from pure association to plausible causality.

- Dr. James Russell

In this recent publication, Drs. James Russell and Keith Walley describe how they used Mendelian randomization to determine death from sepsis is, in part, caused by an increase in clearance of low-density lipoproteins (a droplet composed of lipids and proteins that is used by the body to store and transport fat), rather than simply low levels of these droplets.

This method may be particularly useful in informing the development of targeted treatments for sepsis by using Mendelian randomization to create a better profile of different sepsis sub-types based on the particular pathways that are active or suppressed during sepsis. Clinicians can then use biomarkers to identify which sub-type of sepsis a patient is experiencing and tailor their treatment strategy to that particular sub-type. This can pave the way for improved results for these patients. 

Using Mendelian randomization on large publicly-available data sets can be used to discover molecules that play a central role in causing damage to the brain, heart, lungs, and kidneys in sepsis.  Together with laboratory investigations to deeply understand how these central molecules work, we can develop novel therapies to treat sepsis and prevent its crippling health impacts.

- Dr. Keith Walley

Dr. James (Jim) Russell is currently a Professor of Medicine at the University of British Columbia (UBC) and an Investigator at the Centre for Heart Lung Innovation (HLI) at St Paul’s Hospital. Dr. Russell is the Principal Investigator of the CAPtivate Research program, funded by the Canadian Institutes of Health Research (CIHR), which is studying causes, mechanisms, and treatments for pneumonia. This group includes 47 sites, 25 across Canada and 22 across France. He is also a Co-Lead for the Long COVID Web, which is also funded by CIHR under biomedical research (Pillar 1). 

Dr. Keith Walley, a Professor of Medicine at UBC and the Director of the HLI, focuses his research on understanding the fundamental mechanisms underlying impaired myocardial function and organ dysfunction during inflammatory diseases like sepsis. His work specializes in exploring the genetic factors influencing outcomes in critical illness, particularly regarding inflammatory and innate immunity genes related to systemic inflammatory response syndrome (SIRS), sepsis, and septic shock. As members of the Action on Sepsis Research Cluster, Drs. Russell and Walley are contributing to improving our biological understanding of sepsis and using this knowledge to develop new personalized approaches to managing sepsis care.

  • Research Highlight

First Nations land acknowledegement

Action on Sepsis operates on the traditional, ancestral, and unceded territory of the Coast Salish peoples — xʷməθkʷəy̓əm (Musqueam), Sḵwx̱wú7mesh (Squamish), and Səl̓ílwətaʔ/Selilwitulh (Tsleil-Waututh) Nations. We invite everyone to reflect on the traditional territories and land that they currently work and live on.

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