👤 Marios K Georgakis

Elevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized. We sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996). Lp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality. In young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk. Show less

Clinical trials have shown that interleukin-6 (IL-6) signaling inhibitors reduce lipoprotein(a) [Lp(a)] levels, though the relevance of this reduction to atherosclerotic cardiovascular disease (ASCVD) risk is uncertain. We leveraged Mendelian randomization (MR) to investigate the extent to which Lp(a) reduction mediates the effects of IL-6 signaling inhibition on ASCVD. IL-6 signaling inhibition was proxied by the IL6R variant p.Asp358Ala and scaled to C-reactive protein (CRP) levels. Genetic associations with Lp(a) were obtained from UK Biobank (n = 343,681). Outcomes included large-artery atherosclerotic stroke (LAAS: 6399 cases), carotid plaque (29,760 cases), and coronary artery disease (CAD: 181,522 cases). MR analyses estimated the association of IL-6 signaling inhibition with Lp(a) and ASCVD, and we quantified the proportion of the IL-6-ASCVD association mediated by Lp(a). Individual-level analyses tested whether effects of IL-6 signaling inhibition on Lp(a) and CAD were amplified in carriers of Lp(a)-raising variants. Genetically proxied IL-6 signaling inhibition modestly reduced Lp(a) (-3.01 mg/dL per 1-ln(CRP) reduction, 95% CI -4.79, -1.23) and protected against all ASCVD outcomes (ORs: 0.34-0.69). Lp(a) mediated only a small proportion of the IL-6-ASCVD association (range: 1.3%-4.8%). In carriers of Lp(a)-raising variants, the IL-6-Lp(a) association was stronger (-9.8 mg/dL, 95% CI -14.6, -5.1; p These findings suggest that Lp(a) minimally mediates and does not modify the cardiovascular benefits of IL-6 signaling inhibition, supporting these targets as independent and complementary for ASCVD. The amplified IL-6-Lp(a) association in carriers of Lp(a)-raising variants warrants replication. Show less

Lipoprotein(a) (Lp(a)) is a highly atherogenic lipoprotein and the target of investigational therapies. Using a Mendelian randomization study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and related phenotypes. We obtained genetic associations with Lp(a) levels ( Genetically predicted Lp(a) levels associated with significantly increased risk of all-cause ischemic stroke (odds ratio [OR], 1.04 [95% CI, 1.02-1.07], Elevated Lp(a) is primarily associated with ischemic stroke due to large artery atherosclerosis, while showing no link to cerebral small vessel disease. These findings support prioritization of patients with atherosclerotic cerebrovascular disease in Lp(a)-lowering stroke prevention trials. Show less

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial. Show less