Circulating proteins and risk of small vessel stroke: A two-sample Mendelian randomization study.

To identify promising circulating biomarkers for small vessel stroke (SVS), we applied Mendelian randomization (MR) design to systematically screen circulating proteins for potential development of SVS. We performed two-sample MR analyses to estimate the associations between 4782 human circulating proteins (including immunity-related proteins) and risk of SVS. We selected 359 circulating proteins in MR estimation (4422 circulating proteins with <3 SNPs were excluded) with totally 5368 European descents. Summary statistics for SVS originated from the MEGASTROKE Consortium, involving 446,696 participants. MR analyses were conducted to estimate associations of circulating proteins with SVS. After inverse variance weighting and sensitivity analysis filtration, GRAMD1C causally increased the risk of SVS (OR = 2.86, 95% CI = 1.71-4.76, P = 5.61e-05). In addition, PTGR1 (OR = 1.15, 95% CI = 1.04-1.27, P = 6.65e-03) presented a suggestive association with SVS. In this two-sample MR investigation, a significant association was identified between the cholesterol transporter GRAMD1C and SVS, indicating its potential as a promising target for diagnosis and therapy.