Genetic insights into the risk of metabolic syndrome and its components on stroke and its subtypes: Bidirectional Mendelian randomization

Abstract

The role of metabolic syndrome (MetS) on stroke has been explored only in many observational studies. We conducted Mendelian randomization (MR) to clarify whether or not the genetically predicted MetS and its components are causally associated with stroke and its subtypes. Genetic instruments of MetS and its components and outcome data sets for stroke and its subtypes came from the gene-wide association study in the UK Biobank and MEGASTROKE consortium, respectively. Inverse variance weighting was utilized as the main method. Genetically predicted MetS, waist circumference (WC), and hypertension increase the risk of stroke. WC and hypertension are related to increased risk of ischemic stroke. MetS, WC, hypertension, and triglycerides (TG) are causally associated with the increasing of large artery stroke. Hypertension increased the risk of cardioembolic stroke. Hypertension and TG lead to 77.43- and 1.19-fold increases, respectively, in small vessel stroke (SVS) risk. The protective role of high-density lipoprotein cholesterol on SVS is identified. Results of the reverse MR analyses show that stroke is related to hypertension risk. From the genetical variants perspective, our study provides novel evidence that early management of MetS and its components are effective strategies to decrease the risk of stroke and its subtypes.

Metabolic Traits and Risk of Ischemic Stroke in Japanese and European Populations: A Two-Sample Mendelian Randomization Study

“…In a two-sample MR analyses carried out in a European population (over 400 SNPs included), both SBP and DBP were identified as causal factors in the risk of IS [15]. A bidirectional MR study in a European population showed that hypertension was associated with an increased risk of IS [8]. Further, another MR study on a European population, incorporating in excess of 300 SNPs for analyses, further corroborated its causal association [22].…”

“…Moreover, these metabolic traits are mostly components of metabolic syndrome (MetS), a cluster of abnormal metabolic conditions regarded as an important risk factor for IS. Due to the diversity of its components, which include central obesity, dyslipidemia, increased blood pressure, and high blood glucose (BG) levels, the association of MetS and the metabolic traits with IS has gradually become a concern [4][5][6][7][8]. However, the limitations of traditional epidemiology approaches, combined with the substantial costs associated with conducting randomized controlled trials and comorbidities among metabolic traits and other risk factors, significantly increase the difficulty of inferring a causal relationship between metabolic traits and IS [9].…”

Genetic Insights into the Risk of Metabolic Syndrome and Its Components on Dementia: A Mendelian Randomization

“…All the genetic instrumental variables (IVs) associated with MetS and its five components must meet a significance level at a genome-wide statistical threshold of p < 5×10 -8 . Then, the independent SNPs are identified using the linkage disequilibrium (LD) with the threshold of LD r 2 < 0.05 at a window size of 10,000 Kb [19,20]. In addition, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis is used to detect the potential outlier SNPs accounting for possible pleiotropy [21].…”

Recent advances in mechanistic, therapeutic, and diagnostic research of cerebrovascular diseases: updates from brain & BrainPET 2022

“…Among other findings, they confirmed that genetically predicted metabolic syndrome, waist circumference, hypertension, and triglycerides are associated with an increased risk of large artery stroke. 15 Their observations highlight the importance of early metabolic syndrome management for stroke prevention.…”