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

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) (N cases =51,929, N cntrl =39,980) and subsequent arterial ischemic stroke (AIS) N cases =45,120, N cntrl =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= 3.69x10 -08 ) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77x10 -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.