A Mendelian Randomization Study and Experimental Validation Investigating the Potential Relationship Among
Objective:
This study employs Mendelian randomization (MR) aimed at systematically evaluating the relationship among interleukin-6 receptor subunit beta, obesity, and Alzheimer's disease (AD). We conducted animal studies to validate the reliability of the MR analytical outcomes.
Methods:
The pooled data for the interleukin-6 receptor subunit beta originated from the genome-wide association study (GWAS) dataset, which included a total of 10,534,735 participants. Obesity pooled data were from the GWAS dataset (case n = 23,971 and control n = 388,084) and AD pooled data from the GWAS database (case n = 39,106 and control n = 46,828). The aforementioned data sets facilitated MR causal analysis. First, utilize the inverse variance weighting (IVW) method for analysis and enhance it with MR-Egger regression and weighted median approaches, and a sensitivity analysis was performed by MR-multiple effect residuals and outliers (MR-Presso), Cochran Q test, and Leave-one (LOO) analysis. We established an obesity model by feeding 6-week-old male ApoE-/- mice a high-fat diet for 16 weeks. In contrast, C57BL/6 control mice were fed a normal diet for the same duration. An AD model was established by feeding 3-month-old APP/PS1 mice a normal diet for 24 weeks. We harvested serum and hippocampal tissue from the mice for enzyme-linked immunosorbent assay (ELISA).
Results:
MR analysis indicated that a genetically predicted increase in interleukin-6 receptor subunit beta raises the risk of AD (OR = 1.064, 95% CI: 1.021-1.109, p = 0.003). The exposure factor interleukin-6 receptor subunit beta served as a protective element against obesity (OR = 0.9372,95%CI:0.8921-0.9847, p = 0.010). Obesity showed an adverse relationship with AD. As the body mass index (BMI) increased, the risk of developing AD decreased (OR = 0.9299, 95% CI: 0.8939-0.9674, p ＜0.001). ELISA findings revealed that the levels of interleukin-6 receptor subunit beta (gp130), oncostatin-M (OSM), and IL-6 in serum and hippocampus decreased in obesity, whereas they increased in AD, aligning with the results of the MR Analysis.
Conclusion:
In summary, our extensive Mendelian randomization data suggest that increased levels of the interleukin-6 receptor subunit beta may be associated with a reduced risk of obesity, and consequently, may increase the risk of AD.
Insights
This study found that higher interleukin-6 receptor subunit beta levels are linked to lower obesity risk but increased Alzheimer's disease risk. Animal models supported these Mendelian randomization findings.
Area of Science:
- Neuroscience
- Genetics
- Metabolic Disorders
Background:
- Obesity is a growing global health concern with complex links to neurodegenerative diseases.
- Interleukin-6 receptor subunit beta (IL-6Rβ) plays a role in inflammatory pathways, potentially influencing both metabolic and neurological health.
- Understanding the specific genetic contributions to Alzheimer's disease (AD) risk is crucial for developing targeted interventions.
Purpose of the Study:
- To investigate the causal relationships between interleukin-6 receptor subunit beta, obesity, and Alzheimer's disease using Mendelian randomization.
- To validate Mendelian randomization findings through animal model studies.
Main Methods:
- Mendelian randomization analysis utilizing large-scale genome-wide association study datasets for IL-6Rβ, obesity, and AD.
- Employing inverse variance weighting, MR-Egger regression, and weighted median methods for causal inference.
- Conducting sensitivity analyses with MR-Presso, Cochran Q test, and Leave-One-Out analysis.
- Establishing mouse models for obesity (ApoE-/- mice on high-fat diet) and AD (APP/PS1 mice) to validate findings via ELISA.
Main Results:
- Genetically predicted higher IL-6Rβ levels were associated with an increased risk of AD (OR = 1.064).
- IL-6Rβ was found to be protective against obesity (OR = 0.9372).
- Increased BMI showed a protective association with AD risk (OR = 0.9299).
- ELISA results in animal models showed decreased IL-6Rβ, OSM, and IL-6 in obesity and increased levels in AD models, consistent with MR analysis.
Conclusions:
- Mendelian randomization data suggest that elevated IL-6Rβ levels may reduce obesity risk.
- Conversely, these findings imply that reduced obesity risk associated with IL-6Rβ could potentially increase the risk for Alzheimer's disease.
More Related Videos
05:53Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
07:26High-resolution Melting PCR for Complement Receptor 1 Length Polymorphism Genotyping: An Innovative Tool for Alzheimer's Disease Gene Susceptibility Assessment
Published on: July 18, 2017
Related Concept Videos
01:13Randomized Experiments
Simple randomization
Simple...
01:11Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...