Abstract
The causal effect of insulin resistance on small vessel stroke and Alzheimer's disease (AD) was controversial in previous studies. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect of insulin resistance on small vessel stroke and AD. We selected 12 single-nucleotide polymorphisms (SNPs) associated with fasting insulin levels and five SNPs associated with "gold standard" measures of insulin resistance as instrumental variables in MR analyses. Summary statistical data on SNP-small vessel stroke and on SNP-AD associations were derived from studies by the Multi-ancestry Genome-Wide Association Study of Stroke consortium (MEGASTROKE) and the Psychiatric Genomics Consortium-Alzheimer Disease Workgroup (PGC-ALZ) in individuals of European ancestry. Two-sample MR estimates were conducted with inverse-variance-weighted, robust inverse-variance-weighted, simple median, weighted median, weighted mode-based estimator, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke (OR 1.23, 95% confidence interval [CI] 1.05-1.44, p=0.01 using fasting insulin; OR 1.25, 95% CI 1.07-1.46, p=0.006 using gold standard measures of insulin resistance) and AD (OR 1.13, 95% CI 1.04-1.23, p=0.004 using fasting insulin; OR 1.02, 95% CI 1.00-1.03, p=0.03 using gold standard measures of insulin resistance) using the inverse-variance-weighted method. No evidence of pleiotropy was found using MR-Egger regression. Our findings provide genetic support for a potential causal effect of insulin resistance on small vessel stroke and AD.
Highlights
Cerebral small vascular disease (CSVD) is an age-related pathologic process affecting small arteries, arterioles, venules and capillaries of the brain, of which the prevalence ranging from 5% for people aged 50 years to almost 100% for people aged 90 years.[1, 2] With shared potential risk factors such as abnormal glucose metabolism,[3, 4] CSVD accounts for ~ 45% of dementia cases.[5]
Insulin resistance measured by homeostasis model assessment–estimated insulin resistance (HOMA-IR) index was reported to be positively correlated with silent lacunar stroke,[12] another study found that the insulin resistance score rather than
In our Mendelian randomization (MR) analysis, we evaluated insulin resistance using both body mass index (BMI)-adjusted fasting insulin and gold standard measures, and summary statistics for the association of individual single-nucleotide polymorphisms (SNPs) with small vessel stroke was acquired from the large-scale genome-wide association study (GWAS)-MEGASTROKE consortium
Summary
Cerebral small vascular disease (CSVD) is an age-related pathologic process affecting small arteries, arterioles, venules and capillaries of the brain, of which the prevalence ranging from 5% for people aged 50 years to almost 100% for people aged 90 years.[1, 2] With shared potential risk factors such as abnormal glucose metabolism,[3, 4] CSVD accounts for ~ 45% of dementia cases.[5]. Insulin resistance is a pathological condition resulting from decreased insulin sensitivity both in peripheral and in the brain.[7] It has been well demonstrated that insulin resistance is associated with a risk and poor outcomes of ischemic stroke.[8,9,10] Recently, observational studies have reported that insulin resistance was associated with an increased risk of CSVD.[11,12,13,14] brain insulin resistance was recently demonstrated to play an important role in Alzheimer Disease.[15] the causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous Mendelian randomization (MR) analyses.[16, 17]. The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies
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