The impact of genetic variation within the vitamin D pathway upon skeletal muscle function: A systematic review

Studies in vitro have demonstrated a key molecular role for 1,25-dihydroxyvitamin D (1,25D) in skeletal muscle function, with vitamin D-deficiency (low serum 25-hydroxyvitamin D, 25D) being associated with muscle pain and weakness. Despite this, an understanding of the overall role of vitamin D in muscle health (particularly the impact of vitamin D-related genetic variants) has yet to be fully resolved, relative to more well-studied targets such as the skeleton. Thus, we aimed to review existing studies that have investigated relationships between skeletal muscle function and single nucleotide polymorphisms (SNPs) within vitamin D-related genes. A systematic review of papers published between January 2000 and June 2022 on PubMed, EMBASE and Web of Science pertaining to association between functionally relevant vitamin D receptor genetic variants and variants within genes of the vitamin D pathway and skeletal muscle function/outcomes was performed. 21 articles were included in the review for final analysis, of which 20 only studied genetic variation of the VDR gene. Of the included articles, 81 % solely included participants aged ≥ 50 years and of the 9 studies that did not only include White individuals, only 2 included Black participants. Within the vitamin D system, the VDR gene is the primary gene of which associations between polymorphisms and muscle function have been investigated. VDR polymorphisms have been significantly associated with muscle phenotypes in two or more studies. Of note A1012G was significantly associated with higher handgrip strength, but the results for other SNPs were notably variable between studies. While the lack of definitive evidence and study heterogeneity makes it difficult to draw conclusions, the findings of this review highlight a need for improvements with regards to the use of more diverse study populations, i.e., inclusion of Black individuals and other people of colour, and expanding research scope beyond the VDR gene.