The Role of Dietary Vitamin E in Preventing Degenerative Musculoskeletal Diseases: Insights from Mendelian Randomization

doi:10.21203/rs.3.rs-4950635/v1

Download PDF

Research Article

The Role of Dietary Vitamin E in Preventing Degenerative Musculoskeletal Diseases: Insights from Mendelian Randomization

https://doi.org/10.21203/rs.3.rs-4950635/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Degenerative musculoskeletal diseases, including osteoarthritis, osteoporosis, intervertebral disc degeneration, and sarcopenia, significantly impair patient mobility and quality of life, particularly in the elderly. Despite extensive research, the pathogenesis of these diseases remains incompletely understood, and effective treatments are lacking. Recent evidence suggests that oxidative stress and inflammation play crucial roles in the development of these conditions. Vitamin E, a potent antioxidant, has been proposed as a potential protective factor.

Objective

To investigate the causal relationship between dietary vitamin E intake and the risk of degenerative musculoskeletal diseases using a two-sample Mendelian randomization (MR) approach.

Methods

I utilized data from the UK Biobank's IEU OpenGWAS, the Finnish FinnGen Biobank, and the PhenoScanner database. Genetic variants associated with vitamin E intake were used as instrumental variables. Outcome data for OA, OP, SP, and IVDD were obtained from large-scale genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was the primary analysis, supported by MR-Egger, weighted median, and other sensitivity analyses to ensure robustness.

Results

The IVW method revealed no significant causal association between vitamin E intake and the risk of OA, OP, SP, or IVDD. Sensitivity analyses, including Cochran’s Q test and the MR-Egger intercept test, indicated no evidence of heterogeneity or horizontal pleiotropy. Leave-one-out analyses confirmed that no single SNP significantly influenced the overall causal effect estimates.

Conclusion

This MR study found no evidence to support a causal relationship between dietary vitamin E intake and the risk of degenerative musculoskeletal diseases. These findings suggest that vitamin E supplementation may not be effective in preventing or managing these conditions. Future research should explore other potential factors and consider different populations to further understand the role of vitamin E in musculoskeletal health.

Vitamin E

Antioxidants

Oxidative stress

Degenerative musculoskeletal diseases

Osteoarthritis

Osteoporosis

Intervertebral disc degeneration

Sarcopenia

Mendelian randomization

Degenerative musculoskeletal diseases refer to structural and functional disorders of muscles, bones, cartilage, joints, and surrounding connective tissues, leading to weakness and impaired mobility in patients [1]. Osteoarthritis (OA), osteoporosis (OP), intervertebral disc degeneration (IVDD), and sarcopenia (SP) are common degenerative musculoskeletal diseases, sharing similar age-related risk factors [2–5]. OA is the most common degenerative joint disease globally, characterized by pain and restricted movement, significantly decreasing the quality of life [2,6]. OP is a major public health concern worldwide, characterized by reduced bone mass, microstructural deterioration, decreased bone hardness, and increased risk of fractures [3,7]. IVDD is a leading cause of low back pain and disability, typically attributed to age-related structural damage to the intervertebral disc (IVD) and low-grade inflammation [4,8]. SP is a systemic and progressive skeletal muscle disease, clinically manifesting as accelerated decline in muscle mass and strength, further increasing the risk of functional decline [5]. With the acceleration of global aging, degenerative musculoskeletal diseases are becoming increasingly prevalent, resulting in additional social and economic burdens. Meanwhile, the rapid development of the economy and society has promoted human desires for health and longevity, leading to unprecedented prosperity in aging research [9]. Unfortunately, effective treatments to delay or halt the progression of degenerative musculoskeletal diseases are still lacking in clinical practice. Despite extensive research and significant advances over the past decades, the detailed pathogenesis of degenerative musculoskeletal diseases remains incompletely understood, hindering the research and development of effective and safe therapeutic strategies.

New evidence suggests that oxidative stress and inflammation play crucial roles in the pathogenesis of degenerative musculoskeletal diseases [10–13]. Vitamin E is an effective antioxidant and has been considered a potential protective factor against oxidative damage and inflammatory processes in musculoskeletal tissues [14, 15]. However, the relationship between dietary vitamin E intake and the risk of degenerative musculoskeletal diseases remains unclear and requires further investigation. Observational studies have reported conflicting results regarding the relationship between vitamin E intake and musculoskeletal health outcomes [16]. While some studies suggest a protective effect of vitamin E against osteoporosis, osteoarthritis, lumbar disc degeneration, and sarcopenia [17–21], others have found no significant associations, or even health risks exacerbating degenerative musculoskeletal diseases [22, 23]. These inconsistencies may be due to inherent methodological limitations in observational study designs, such as confounding factors and measurement errors. To address these limitations and clarify the causal relationship between dietary sources of vitamin E and degenerative musculoskeletal diseases, we conducted a two-sample Mendelian randomization study. Mendelian randomization is a method that uses genetic variants related to the exposure of interest (in this case, vitamin E intake) as instrumental variables to assess causal relationships in observational studies [24]. By leveraging genetic data from large-scale genome-wide association studies, Mendelian randomization can provide more reliable evidence for the causal impact of vitamin E intake on musculoskeletal health outcomes [25].

In this article, the results of the Mendelian randomization study are presented and its implications for public health and clinical practice are discussed. The strengths and limitations of the study are also highlighted, along with proposed directions for future research in this field. The findings aim to contribute to a better understanding of the role of vitamin E in musculoskeletal health and provide information for strategies to prevent and manage these debilitating diseases.

2.1 Study Design

This study utilized a two-sample Mendelian randomization (MR) approach to investigate the causal relationship between vitamin E and degenerative musculoskeletal diseases (osteoarthritis, osteoporosis, muscle loss, and intervertebral disc degeneration). Vitamin E was considered the exposure factor, while degenerative musculoskeletal diseases (osteoarthritis, osteoporosis, muscle loss, and intervertebral disc degeneration) were the outcome variables. Figure 1 outlines the study design and the hypotheses of the MR study [24].

2.2 Data Sources

Biological information databases used in this study primarily included the UK Biobank's IEU OpenGWAS, the Finnish FinnGen Biobank, and the PhenoScanner database. Exposure data for vitamin E were obtained from the IEU GWAS database, with the ID ukb-b-12506, involving 13,548 participants and 9,851,867 SNPs. Outcome data for degenerative musculoskeletal diseases (osteoarthritis, osteoporosis, muscle loss, and intervertebral disc degeneration) were obtained from the IEU GWAS database and the Finnish database. See Table 1 for specific details. The genetic backgrounds of the study populations were all from Europeans to eliminate bias due to racial-related confounding factors.

Table 1 A detailed description of the GWAS data involved in this study.

2.3 Instrumental Variable Selection

When selecting instrumental variables (IVs), three main assumptions must be met: 1) strong correlation with the exposure factor; 2) no direct correlation with the outcome through confounding pathways; and 3) only indirect correlation with the outcome through the exposure. Using a significance threshold of P < 1×10-6, statistically significant SNP loci were selected as initial IVs from the genetic data on vitamin E. Linkage disequilibrium was set at r2 = 0.001 with a region width of 10,000 kb to ensure independence among SNPs and exclude the influence of genetic pleiotropy on the results. PhenoScanner V2 database was used to identify and remove confounding SNPs (e.g., those related to smoking, alcohol consumption, obesity) to meet the second assumption. Additionally, SNPs closely related to the outcome (P < 1×10-6) were excluded. Finally, the strength of the instrumental variables was quantified using the F-statistic, calculated as (beta/se)². An F-statistic greater than 10 indicates a low likelihood of weak instrumental variable bias [26].

2.4 MR Analysis

The inverse variance weighted-fixed effects model (IVW-FE) was used as the main MR analysis method. IVW-FE is the most effective analysis method when there is no genetic pleiotropy, meaning the SNPs selected as instrumental variables do not affect the outcome through any pathways other than the exposure. Additionally, MR-Egger regression, Weighted median, Weighted mode, and Simple mode were used for result validation and stability testing. The simple median method requires at least 50% of genetic variation to be effective instrumental variables, while the weighted median method requires that the weights contributed by genetic variation be at least 50% effective. MR Egger regression relaxes the requirement of no genetic pleiotropy in the IVW method, assuming that instrumental variables do not or only partially affect the outcome through the exposure factor [25,27].

2.5 Sensitivity Analysis

Sensitivity analysis included calculating the F-statistic for SNPs to assess the strength of the association between instrumental variables and exposure factors, where F= (beta/se)², with beta being the allele effect value and se being the standard error. An F-value less than 10 indicates potential weak instrumental variable bias and the SNP should be removed. Cochran's Q test was used to assess heterogeneity among instrumental variables, with a P-value > 0.05 suggesting a low likelihood of heterogeneity. The MR Egger intercept test was used to assess the presence of horizontal pleiotropy, with a statistically significant intercept indicating significant horizontal pleiotropy in the study. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) method were used to detect and correct for outliers if they exist. The "leave-one-out" sensitivity analysis was conducted by removing individual SNPs each time to assess the impact of each genetic variant on the overall causal effect [25,28].

2.6 Statistical Methods

All statistical analyses were performed using the "TwoSampleMR" package in R software version 4.2.2. Results were presented as odds ratios (OR) with 95% confidence intervals (CI). The significance level was set at α=0.05.

3.1 Causal Association between Vitamin E and Osteoarthritis (OA)

In the analysis of the causal association between vitamin E and osteoarthritis (OA), a total of 14 valid SNPs were included, all with F-values greater than 10, indicating strong instrumental variables. The IVW method analysis showed no causal association between vitamin E intake and OA. Similarly, the MR-Egger method indicated no causal association between vitamin E intake and OA. Heterogeneity analysis using the IVW test (Q=15.05832, P=0.3037259) and MR-Egger test (Q=15.04742, P=0.2388533) did not reveal significant heterogeneity. No outliers were found in the MR-PRESSO analysis. The MR-Egger regression analysis suggested no evidence of horizontal pleiotropy (intercept= -7.608735e-05, P=0.9272518). Leave-one-out analysis showed that no single SNP significantly influenced the overall effect estimate. (See Figure 2 for detailed results)

3.2 Causal Association between Vitamin E Supplements and Osteoporosis (OP)

In the analysis of the causal association between vitamin E supplements and osteoporosis (OP), a total of 14 valid SNPs were included, all with F-values greater than 10, indicating strong instrumental variables. The IVW method analysis showed no causal association between vitamin E supplement intake and osteoporosis. Similarly, the MR-Egger method indicated no causal association between vitamin E supplement intake and osteoporosis. Heterogeneity analysis using the IVW test (Q=14.80111, P=0.3199331) and MR-Egger test (Q=14.08452, P=0.2953436) did not reveal significant heterogeneity. No outliers were found in the MR-PRESSO analysis. The MR-Egger regression analysis suggested no evidence of horizontal pleiotropy (intercept=-0.0003, P=0.4497). Leave-one-out analysis showed that no single SNP significantly influenced the overall effect estimate. (See Figure 3 for detailed results)

3.3 Causal Association between Vitamin E Supplements and Sarcopenia (SP)

According to the IVW (inverse variance weighted) analysis, vitamin E supplements had no causal effect on the increase in lean mass of the appendicular limbs, grip strength, or walking speed. Similar results were obtained using other Mendelian randomization methods such as MR-Egger and weighted median MR models. To assess the robustness and reliability of these results, Cochran’s Q test, MR-Egger intercept test, and leave-one-out analysis were performed. The Cochran’s Q test had P-values greater than 0.05, indicating no detected heterogeneity. All MR-Egger intercept tests had P-values greater than 0.05, indicating no evidence of horizontal pleiotropy. (See Figure 4 for detailed results) Leave-one-out analysis showed that no single nucleotide polymorphism (SNP) significantly affected the results, meaning that the removal of any SNP would not significantly affect the results. (See Supplementary Figure 1 for detailed results)

3.4 Causal Association between Vitamin E Supplements and Intervertebral Disc Degeneration (IVDD)

In the analysis of the causal association between vitamin E supplements and intervertebral disc degeneration (IVDD), a total of 13 valid SNPs were included, all with F-values greater than 10, indicating strong instrumental variables. The IVW method analysis showed no causal association between vitamin E supplement intake and IVDD. Similarly, the MR-Egger method indicated no causal association between vitamin E supplement intake and IVDD. Heterogeneity analysis using the IVW test (Q=13.51499, P=0.3327453) and MR-Egger test (Q=13.50319, P=0.2617118) did not reveal significant heterogeneity. No outliers were found in the MR-PRESSO analysis. The MR-Egger regression analysis suggested no evidence of horizontal pleiotropy (intercept= -0.00112839, P=0.9236775). Leave-one-out analysis showed that no single SNP significantly influenced the overall effect estimate.

Degenerative musculoskeletal diseases such as osteoarthritis, osteoporosis, intervertebral disc degeneration, and sarcopenia are common in the elderly population, significantly affecting patients' quality of life and imposing a substantial burden on society and the economy. This study employed a Mendelian randomization (MR) study design to investigate the effect of vitamin E on degenerative musculoskeletal diseases. The results indicated no significant causal relationship between vitamin E intake and osteoarthritis, osteoporosis, sarcopenia, or intervertebral disc degeneration. This finding contrasts with some observational studies that have suggested a protective effect of vitamin E against these diseases.

In this study, we selected strong instrumental variables for MR analysis and conducted various sensitivity analyses, which yielded robust results. This suggests that our conclusions are reasonably reliable. However, the study also has limitations. Firstly, the results of MR studies depend on the rationality and effectiveness of the instrumental variables chosen. Although we adopted strict criteria for selecting instrumental variables, potential biases may still exist. Secondly, our study population mainly consisted of Europeans, and there may be ethnic differences, so our conclusions may not be generalizable to other populations. Additionally, our study only considered vitamin E intake and did not consider other factors related to vitamin E, such as the source and form of vitamin E. Therefore, future research could further explore the impact of these factors on degenerative musculoskeletal diseases.

In conclusion, this study did not find a causal relationship between vitamin E intake and degenerative musculoskeletal diseases. This result has implications for guiding the public in vitamin E intake and the prevention of degenerative musculoskeletal diseases. However, there are still many unknown factors that need further research to more comprehensively understand the impact of vitamin E on musculoskeletal health.

Author Contribution

Wei has completed the entire manuscript.

Funding Sources

No funding sources for this study.

Data and data sharing

Data generated at a large-scale facility. The data underlying this article were accessed from the GWAS Catalog (https:/gwas.mrcieu.ac.uk/https:/www.finngen.f/en). This study's data is freely available online. The R code for this study will be uploaded as an attachment and is freely available.

Conflicts of Interest

The author declares that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

I would like to thank the participants and investigators of the GWAS studies included in this Mendelian randomization analysis. I also acknowledge the researchers and consortia that contributed to the GWAS Catalog and PhenoScanner V2 database, which provided the data used in this study.

Wen ZQ, Lin J, Xie WQ, Shan YH, Zhen GH, Li YS. Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases. Mil Med Res. 2023;10(1):54.
Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376-87.
Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194(2 Suppl):S3-11.
Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44-56.
Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet. 2019;393(10191):2636-46.
Rellmann Y, Eidhof E, Dreier R. Review: ER stress-induced cell death in osteoarthritic cartilage. Cell Signal. 2021;78:109880.
Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med. 2016;374(3):254-62.
Francisco V, Pino J, González-Gay M, Lago F, Karppinen J, Tervonen O, et al. A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol. 2022;18(1):47-60.
Song Y, Wu Z, Zhao P. The Function of Metformin in Aging-Related Musculoskeletal Disorders. Front Pharmacol. 2022;13:865524.
Sanchez-Lopez E, Coras R, Torres A, Lane NE, Guma M. Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol. 2022;18(5):258-75.
Karin M, Clevers H. Reparative inflammation takes charge of tissue regeneration. Nature. 2016;529(7586):307-15.
Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science. 2017;356(6342):1026-30.
Yang L, Bhujel B, Hou Y, Luo J, An SB, Han I, et al. Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold. Adv Mater. 2023;35(41):e2303021.
Chung E, Mo H, Wang S, Zu Y, Elfakhani M, Rios SR, et al. Potential roles of vitamin E in age-related changes in skeletal muscle health. Nutr Res. 2018;49:23-36.
Saud Gany SL, Chin KY, Tan JK, Aminuddin A, Makpol S. Preventative and therapeutic potential of tocotrienols on musculoskeletal diseases in ageing. Front Pharmacol. 2023;14:1290721.
McAlindon TE, Jacques P, Zhang Y, Hannan MT, Aliabadi P, Weissman B, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996;39(4):648-56.
Liang G, Kow ASF, Tham CL, Ho YC, Lee MT. Ameliorative Effect of Tocotrienols on Perimenopausal-Associated Osteoporosis-A Review. Antioxidants (Basel). 2022;11(11).
Zhou P, Shao R, Wang H, Miao J, Wang X. Dietary vitamin A, C, and E intake and subsequent fracture risk at various sites: A meta-analysis of prospective cohort studies. Medicine (Baltimore). 2020;99(35):e20841.
Mathieu S, Soubrier M, Peirs C, Monfoulet LE, Boirie Y, Tournadre A. A Meta-Analysis of the Impact of Nutritional Supplementation on Osteoarthritis Symptoms. Nutrients. 2022;14(8).
Khor SC, Abdul Karim N, Ngah WZ, Yusof YA, Makpol S. Vitamin E in sarcopenia: current evidences on its role in prevention and treatment. Oxid Med Cell Longev. 2014;2014:914853.
Chin KY, Ima-Nirwana S. The Role of Vitamin E in Preventing and Treating Osteoarthritis - A Review of the Current Evidence. Front Pharmacol. 2018;9:946.
Ochi H, Takeda S. The Two Sides of Vitamin E Supplementation. Gerontology. 2015;61(4):319-26.
Chin KY, Ima-Nirwana S. The effects of α-tocopherol on bone: a double-edged sword? Nutrients. 2014;6(4):1424-41.
Sanderson E, Glymour MM, Holmes MV, Kang H, Morrison J, Munafò MR, et al. Mendelian randomization. Nat Rev Methods Primers. 2022;2.
Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. Bmj. 2018;362:k601.
Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658-65.
Skrivankova VW, Richmond RC, Woolf BAR, Davies NM, Swanson SA, VanderWeele TJ, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. Bmj. 2021;375:n2233.
Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. Jama. 2021;326(16):1614-21.

No competing interests reported.

Rcode.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

The Role of Dietary Vitamin E in Preventing Degenerative Musculoskeletal Diseases: Insights from Mendelian Randomization

Status:

Version 1

Abstract

Background

Objective

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials and Methods

3. Results

4. Discussion

Declarations

Author Contribution

Funding Sources

Data and data sharing

Conflicts of Interest

Acknowledgments

References

Additional Declarations

Supplementary Files

Status:

Version 1