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Background
The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies.
Methods
We selected 12 single-nucleotide polymorphisms (SNPs) associated with body mass index (BMI)-adjusted fasting insulin levels and 5 SNPs associated with gold standard measures of insulin resistance as instrumental variables in Mendelian randomization (MR) analyses. Summary statistical data of SNP-small vessel stroke and of SNP-AD associations were derived from the Multi-ancestry Genome-Wide Association Study of Stroke Consortium and Psychiatric Genomics Consortium-Alzheimer’s Disease Workgroup data of 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 methods.
Results
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 BMI-adjusted fasting insulin; OR 1.25; 95% CI 1.07–1.46; P = 0.006 using gold standard measure of insulin resistance) and AD (OR 1.13; 95% CI 1.04–1.23; P = 0.004 using BMI-adjusted 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.
Conclusion
Our findings provide genetic support for a causal effect of insulin resistance on small vessel stroke and AD. Further investigation on the involved mechanisms is needed.
Keywords
Insulin resistance, Small vessel, Alzheimer’s Disease, Mendelian randomization
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Original investigation
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
View the published article at European Journal of Neurology.
Version 1
Posted 25 Feb, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at European Journal of Neurology.
Background
The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies.
Methods
We selected 12 single-nucleotide polymorphisms (SNPs) associated with body mass index (BMI)-adjusted fasting insulin levels and 5 SNPs associated with gold standard measures of insulin resistance as instrumental variables in Mendelian randomization (MR) analyses. Summary statistical data of SNP-small vessel stroke and of SNP-AD associations were derived from the Multi-ancestry Genome-Wide Association Study of Stroke Consortium and Psychiatric Genomics Consortium-Alzheimer’s Disease Workgroup data of 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 methods.
Results
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 BMI-adjusted fasting insulin; OR 1.25; 95% CI 1.07–1.46; P = 0.006 using gold standard measure of insulin resistance) and AD (OR 1.13; 95% CI 1.04–1.23; P = 0.004 using BMI-adjusted 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.
Conclusion
Our findings provide genetic support for a causal effect of insulin resistance on small vessel stroke and AD. Further investigation on the involved mechanisms is needed.
Figure 1
Figure 2
Figure 3
Figure 4
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