Genetic Variants, Serum 25-Hydroxyvitamin D Levels, and Sarcopenia: A Mendelian Randomization Analysis

Abstract

Importance: Vitamin D deficiency is commonly associated with sarcopenia; however, the latest International Clinical Practice Guidelines for Sarcopenia do not recommend vitamin D supplementation for sarcopenia owing to a lack of an apparent therapeutic effect on the indices of sarcopenia among participants with replete vitamin D concentration (ie, 25-hydroxyvitamin D [25(OH)D] level >20 ng/mL) from randomized clinical trials. While there is consensus in all vitamin D guidelines that serum levels of 25(OH)D less than 10 ng/mL should be corrected, approximately 30% of the world population's 25(OH)D levels range from 10 to 20 ng/mL, and it remains unclear whether such suboptimal levels can maintain optimal health, including sarcopenia risk.

Objective: To investigate the association of serum 25(OH)D level, especially suboptimal levels, with sarcopenia risk.

Design, setting, and participants: This genome-wide genetic association study was performed from August 2022 to February 2023 among the 295 489 unrelated European participants from the UK Biobank (2006-2010). Nonlinear and standard mendelian randomization analyses were used to examine the association of serum 25(OH)D concentration with sarcopenia risk.

Exposures: A weighted genetic risk score using 35 unrelated single-nucleotide variants from the UK Biobank and weights from the SUNLIGHT Consortium was selected as an instrumental variable for serum 25(OH)D concentration.

Main outcomes and measures: The primary outcome was sarcopenia, and the secondary outcomes consisted of grip strength, appendicular lean mass index, and gait speed.

Results: The final genetic analyses included 295 489 participants (mean [SD] age, 56.3 [8.1] years; 139 216 female [52.9%]). There was an L-shaped association between genetically predicted serum 25(OH)D concentration and sarcopenia risk. The risk of sarcopenia decreased rapidly as 25(OH)D concentration increased until 20 ng/mL and then leveled off. The odds ratio of sarcopenia for serum 25(OH)D level of 10 vs 20 ng/mL was 1.74 (95% CI, 1.17-2.59). Similar patterns were also observed when the association between serum 25(OH)D concentration and risks of each of the sarcopenia indices were evaluated.

Conclusions and relevance: In this mendelian randomization genetic association study of adults in the UK Biobank, the findings supported a nonlinear association between suboptimal 25(OH)D levels and sarcopenia risk. Randomized clinical trials among participants with suboptimal 25(OH)D levels are required to verify the potential causality.

Figure 1.. Flowchart of Participant Selection in the UK Biobank

25(OH)D indicates 25-hydroxyvitamin D.

Figure 2.. Phenotypic Associations of Serum 25-Hydroxyvitamin D (25[OH]D) With Risk of Sarcopenia Traits

Phenotypic associations of serum 25(OH)D concentration with sarcopenia (A), grip strength (B), appendicular lean mass index (C), and slow gait speed (D). A total of 233 007 participants were included in the observational analyses for sarcopenia, grip strength, and appendicular lean mass index, and 232 271 participants for slow gait speed. To convert nmol/L to ng/mL, divide by 2.496. Shaded areas indicate 95% CIs; OR, odds ratio.

Figure 3.. Genetic Associations of Serum 25-Hydroxyvitamin D (25[OH]D) With Risk of Sarcopenia Using 35 Single-Nucleotide Variants to the Instrument

Genetic associations of serum 25(OH)D concentration with sarcopenia (A), grip strength (B), appendicular lean mass index (C), and slow gait speed (D). The orange dot represents the reference point of serum 25(OH)D of 50 nmol/L (to convert to ng/mL, divide by 2.496). The adjustment included age, age squared, sex, assessment center, birth location, top 20 genetic principal components, genotyping array in both stages, and nuisance factors that could affect serum 25(OH)D measurements, including the month when the blood sample was taken, fasting time before the blood sample was taken, and sample aliquots for measurement. A total of 295 489 participants were included in the genetic analyses for sarcopenia, grip strength, and appendicular lean mass index, and 293 119 participants for slow gait speed. Shaded areas indicate 95% CIs; OR, odds ratio.