Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank

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.