Genetically Determined Serum 25-Hydroxyvitamin D Is Associated with Total, Trunk, and Arm Fat-Free Mass: A Mendelian Randomization Study

R Kirwan,I G Davies,M Mazidi,M Isanejad

doi:10.1007/s12603-021-1696-1

Abstract

PurposeLow serum vitamin D status has been associated with reduced muscle mass in observational studies although the relationship is controversial and a causal association cannot be determined from such observations. Two-sample Mendelian randomization (MR) was applied to assess the association between serum vitamin D (25(OH)D) and total, trunk, arm and leg fat-free mass (FFM).MethodsMR was implemented using summary-level data from the largest genome-wide association studies (GWAS) on vitamin D (n=73,699) and total, trunk, arm and leg FFM. Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis.ResultsGenetically higher serum 25(OH)D levels had a positive effect on total (IVW = Beta: 0.042, p = 0.038), trunk (IVW = Beta: 0.045, p = 0.023) and arm (right arm IVW = Beta: 0.044, p = 0.002; left arm IVW = Beta: 0.05, p = 0.005) FFM. However, the association with leg FFM was not significant (right leg IVW = Beta: 0.03, p = 0.238; left leg IVW = Beta: 0.039, p = 0.100). The likelihood of heterogeneity and pleiotropy was determined to be low (statistically non-significant), and the observed associations were not driven by single SNPs. Furthermore, MR pleiotropy residual sum and outlier test did not highlight any outliers.ConclusionsOur results illustrate the potentially causal, positive effect of serum 25(OH)D concentration on total, trunk and upper body appendicular fat-free mass.

Highlights

Vitamin D is an essential nutrient for human health with roles in multiple biological pathways and low vitamin D status is associated with multiple chronic diseases [1] as well as being associated with musculoskeletal health [2, 3] highlighting this nutrient’s significance in the global burden of disease
Muscle mass loss has been associated with a multitude of chronic conditions including cardiovascular disease (CVD) [9], type 2 diabetes mellitus (T2DM) [10], increased risk of falls and fractures [11], cognitive decline and depression [12, 13], and all-cause mortality [14]
Mendelian randomization (MR) analysis uses functional polymorphisms (single nucleotide polymorphisms (SNPs)) associated with specific changes in exposures (in this case, serum 25(OH) D) as genetic instruments to determine whether the risk factor is a cause of the disease [21]

Summary

Introduction

Vitamin D is an essential nutrient for human health with roles in multiple biological pathways and low vitamin D status is associated with multiple chronic diseases [1] as well as being associated with musculoskeletal health [2, 3] highlighting this nutrient’s significance in the global burden of disease. Epidemiological studies suggest an association between low vitamin D status and reduced muscle mass [3, 17, 18] some studies have found no such association [19, 20]. Such studies are limited as observational data cannot determine whether an association is causal. Mendelian randomization (MR) analysis uses functional polymorphisms (single nucleotide polymorphisms (SNPs)) associated with specific changes in exposures (in this case, serum 25(OH) D) as genetic instruments to determine whether the risk factor is a cause of the disease [21]. MR analysis may circumvent the financial, logistical and ethical limitations of randomised controlled trials (RCTs) and the data from such studies can inform the design of pilot RCTs and clinical trials by providing information for the potential magnitude of effect of nutrients on a given outcome in specific populations [23]

Results

Discussion

Conclusion