Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

Abstract

Objective Observational studies point to an inverse correlation between low‐density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high‐density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results We identified 410, 339, 393, and 317 lipid‐related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10‐100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56–66

Mendelian Randomization in Stroke: A Powerful Approach to Causal Inference and Drug Target Validation

“…Along this lines, found a strong positive association between LDL-C and ischemic stroke and a strong inverse association with ICH in participants of the China Kadoorie Biobank. This inverse association between genetically determined LDL-C levels and the risk of ICH was confirmed in cohorts of European descent by Falcone et al (2020). The latter two studies confirmed previous observational results that suggested that very low LDL-C levels increase the risk of ICH (Wang et al, 2013;Saliba et al, 2018;Ma et al, 2019), pointing to novel pathways in ICH.…”

Milk and Fermented Milk Consumption and Risk of Stroke: Longitudinal Study

“…High concentrations of low-density lipoprotein (LDL) cholesterol have been associated with an increased risk of cerebral infarction but with a lower risk of hemorrhagic stroke [ 29 , 30 ]. An inverse association of milk product consumption with LDL to high-density lipoprotein cholesterol ratio has earlier been observed in a study of 70-year-old men [ 31 ].…”

Plant-based diets and long-term health: findings from the EPIC-Oxford study

“…The point estimate for haemorrhagic stroke in vegans compared to meat-eaters was 1⋅35, but this was not statistically significant. The cause of the higher risk of haemorrhagic stroke in vegetarians is not known, but it might be explained by the low LDL-cholesterol which has been associated with an increased risk in observational studies, Mendelian randomisation analyses and in lipid lowering trials using statins (21,22) ; it might also be related to other factors such as high homocysteine due to low vitamin B 12 , or possibly related to the low intake of animal protein, but further research is needed to examine these hypotheses.…”