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Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank
Andrew Elmore1,2, Nimish Adhikari3,4, April E Hartley1,2
1NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol.
Insights
Stroke survivors face higher cardiovascular risks. Genetic studies identified two proteins, CCL27 and TNFRSF14, influencing subsequent cardiovascular events, suggesting inflammation as a key factor and potential therapeutic targets.
Area of Science:
- Genetics
- Cardiovascular Research
- Inflammation Biology
Background:
- Individuals with a history of stroke or transient ischemic attack (TIA) have an increased risk of subsequent cardiovascular events.
- Identifying genetic and molecular risk factors is crucial for developing targeted therapies to improve outcomes after stroke.
Approach:
- Genome-wide association studies (GWAS) were conducted on large cohorts (Million Veteran Program and UK Biobank) to identify genetic variants associated with major adverse cardiovascular events (MACE) and arterial ischemic stroke (AIS) post-stroke.
- Mendelian randomization (MR) was employed using protein quantitative trait loci (pQTLs) to assess the causal effect of 1,463 plasma protein abundances on subsequent MACE.
Key Points:
- Two genetic variants were significantly associated with subsequent cardiovascular events: rs76472767 (AIS) and rs13294166 (MACE).
- Mendelian randomization identified two proteins, CCL27 and TNFRSF14, that influence subsequent MACE after stroke, with roles in inflammation.
- These identified proteins did not show association with incident AIS, suggesting a specific role in post-stroke cardiovascular risk.
Conclusions:
- Two proteins, CCL27 and TNFRSF14, appear to influence subsequent MACE after incident AIS, despite minimal impact on incident stroke risk.
- These findings implicate inflammation as a significant contributor to MACE following AIS.
- The study highlights CCL27 and TNFRSF14 as potential novel therapeutic targets for mitigating cardiovascular risk in stroke survivors.
Background:
Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke.
Methods:
We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (Ncases=51,929, Ncntrl=39,980) and subsequent arterial ischemic stroke (AIS) Ncases=45,120, Ncntrl=46,789) after first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (pQTLs) to determine the effect of 1,463 plasma protein abundances on subsequent MACE using Mendelian randomization (MR).
Results:
Two variants were significantly associated with subsequent cardiovascular events: rs76472767 (OR=0.75, 95% CI = 0.64-0.85, p= 3.69×10-08) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77×10-08) with subsequent MACE. Using MR, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 (effect OR= 0.77, 95% CI = 0.66-0.88, adj. p=0.05), and TNFRSF14 (effect OR=1.42, 95% CI = 1.24-1.60, adj. p=0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation.
Conclusions:
We found evidence that two proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.
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