Gene Variants Predicting Stroke Recovery Outcomes
Post by Natalia Ladyka-Wojcik
The takeaway
For stroke survivors, factors such as age, baseline health, and stroke severity have been highlighted as important when predicting recovery outcomes, but a key factor – genetics – has received much less attention to date. Yet, there may be specific gene variants that can help to predict the cognitive and emotional trajectories of recovery for stroke survivors, providing instrumental insights into future therapeutic approaches.
What's the science?
The outcomes of stroke are long-term, with patients often experiencing a range of cognitive and emotional changes that impact quality of life. A wealth of previous research has investigated genetic factors associated with stroke risk and severity, but there has been considerably less exploration into genetic associations with stroke recovery. Although treatments for stroke patients are becoming more targeted, including the promotion of neural repair, we still understand very little in terms of how genetics may interact with the success of these treatments. Importantly, in order to link specific genetic variants to post-stroke outcomes, researchers also need to identify ways of measuring these outcomes beyond a single index of global disability. This week in Stroke, Cramer and colleagues analyzed three candidate gene variants to determine their potential associations with a series of key motor and functional measures in stroke recovery.
How did they do it?
The authors analyzed genetic data and recovery outcomes from a large-scale, prospective cohort study called STRONG (Stroke, sTress, RehabilitatiON, and Genetics) including more than 750 adult patients with stroke across 28 US stroke centers. Specifically, they examined patients for a period of 1-year post-stroke, to identify genetic variants associated with motor and functional outcomes, as well as stress-related outcomes. At the initial timepoint of the study, the authors collected saliva samples for DNA genotyping analysis. This DNA analysis considered the genetic ancestry of patients, and candidate gene variants were selected based on prior research linking them to specific motor, functional, or stress-related outcomes. For motor and functional outcomes, they selected ApoE ε4 carrier status and brain-derived neurotrophic factor (BDNF) polymorphism, which have both been tied to reduced neural repair in past research. They also selected a dopamine polygenic score (i.e., a characteristic influenced by two or more genes) which models the neurotransmission of dopamine in the human brain. Together, these selected gene variants were analyzed in terms of their predictive relationship to longitudinal outcomes in grip strength, global functional daily living, depression, and cognitive status. Finally, for stress-related outcomes, the authors investigated seven additional gene variants in relation to post-traumatic stress disorder (PTSD) and depression across several timepoints of the longitudinal study. To bolster their results, the authors considered stroke subtypes (which can vary in their symptoms and underlying causes) and also conducted a replication analysis to compare their results to two other previously published, large-scale cohort studies.
What did they find?
For functional outcomes, the authors found that BDNF polymorphism was associated with poorer cognition in stroke patients, as well as reduced grip strength when considering the time from stroke onset to study enrollment. APOE status and dopamine polygenic scores were not found to be related to their measured outcomes, further highlighting the precision with which targeted therapies need to consider whether or not a gene factors into stroke recovery. For stress-related outcomes, the authors identified two of the seven gene variants contributed to poorer outcomes in terms of PTSD and depression, while another one contributed to better outcomes in terms of PTSD and depression. Importantly, stress-related gene variants also broadly varied with the level of post-stroke stress experienced by patients. These genetic associations were found to be important regardless of stroke subtype and most critically, were only evident at 1-year post-stroke but not earlier. As the authors point out, this is why it is important to consider genetic variants not just at the initial stages of recovery but rather in the long term. Finally, their findings successfully replicated results from another large-scale genetic study of post-stroke outcomes, with a genetic variant involved in the expression of a protein associated with brain plasticity predicting global post-stroke outcomes in both studies.
What's the impact?
This study found that comprehensive genetic phenotyping after stroke holds key insights into predicting long-term outcomes for patients. Notably, this study provides a deeper understanding of post-stroke recovery than mere global outcomes scores, by measuring specific functional, motor, and stress-related outcomes and also by considering how much stress the patients reported experiencing. Altogether, these insights could help develop future tailored therapies for patients and potentially identify patients who may need more support to achieve better post-stroke recovery based on genetic risk.