Abstract TP176: Lipids, Apolipoproteins And CSVD: A Mendelian Randomization Study

Aims: The role of dyslipidemia in cerebral small vessel disease (CSVD) has not been well established. Our primary aim was to apply the Mendelian randomization (MR) design to investigate the associations of lipid and apolipoprotein traits with CSVD manifestations. We also used drug target MR to analyze the effects of lipid-modifying strategies on the outcomes. Methods and Results: We conducted a Two-sample MR analysis using the levels of HDL-C, LDL-C, TG, ApoB and ApoA-I as exposures and CSVD manifestations including lacunar strokes, cerebral microbleeds (CMBs) and white matter integrity as outcomes. In addition, we analyzed the effects of TG lowering and LDL-C lowering genetic variants on CSVD manifestations. In univariable MR, increases in HDL-C reduce the occurrence of lacunar strokes (OR: 0.86; 95% CI: 0.76-0.99; p=0.03), increases in TG (OR: 0.73; 95% CI: 0.54,0.99; p=0.04) and ApoA-I (OR: 0.61; 95% CI: 0.46-0.83; p=0.001) respectively reduce all and deep CMBs, elevated ApoA-I levels were associated with lower FA (β: -0.381; 95% CI: -0.72, -0.04; p=0.028) and higher MD (β: 0.386; 95% CI: 0.02, 0.75; p=0.036). Multivariable MR revealed that HDL-C could help prevent lacunar strokes (OR: 0.86; 95% CI: 0.34-0.91; p=0.019), elevated ApoA-I was related to lower risk of both lobar (OR: 0.37; 95% CI: 0.18, 0.79; p=0.01) and deep (OR: 0.31; 95% CI: 0.10, 0.95; p=0.04) CMBs while HDL-C lead to higher risk of lobar CMBs (OR: 2.70; 95% CI: 1.32, 5.49; p=0.006), ApoA-I (β: -0.23; 95% CI: -0.41, -0.05; p=0.013) and HDL-C (β: 0.19; 95% CI: 0.01, 0.36; p=0.034) were closely related to WMH. Besides, increases in LDL-C (OR: 0.26; 95% CI: 0.07, 0.99; p=0.049) and TG (OR: 0.63; 95% CI: 0.46, 0.88; p=0.007) both lead to lower risk of lobar CMBs. Drug-target MR indicated that both LDL-C lowering and TG lowering therapies might help prevent CSVD manifestations. Conclusions: CSVD manifestations are associated with conventional lipids levels as well as apolipoproteins and certain lipid-modifying strategies could help alleviate CSVD manifestations.