The Role of Polymorphisms in Vitamin D-Related Genes in Response to Vitamin D Supplementation

Abstract

Background. Vitamin D deficiency represents a major healthcare problem. Vitamin D status is influenced by genetic and environmental determinants. Several observational studies have evaluated the association of single-nucleotide polymorphisms (SNPs) in vitamin D-related genes and vitamin D levels. Nevertheless, little is known about the role of these SNPs in the response to vitamin D supplementation. We conducted an interventional study to define the association between SNPs in vitamin D-related genes and the response to vitamin D supplementation in 100 self-reported healthy women of Arab ancestry for the majority. Methods. A total of 100 healthy female subjects received a weekly oral dose of 50,000 IU vitamin D for 12 weeks. Serum vitamin D concentration and metabolic profiles were measured at baseline and 12 weeks post-vitamin D supplementation. The genotypes of 37 SNPs selected from previously reported vitamin D-related genes have been assessed by Fluidigm genotyping assay. Results. Rs731236 (VDR gene) and rs7116978 (CYP2R1 gene) showed a significant association with vitamin D status. The rs731236 GG genotype and the rs7116978 CC genotype were associated with a “vitamin D sufficiency” state. Rs731236 GG and rs7116978 CC genotypes showed a higher response to vitamin D supplementation. Transcription factor binding site prediction analysis showed altered binding sites for transcription factors according to the different rs7116978 alleles. Interestingly, the 37 SNPs previously established to play a role in vitamin D-related pathways explained very little of the response to vitamin D supplementation in our cohort, suggesting the existence of alternative loci whose number and effect size need to be investigated in future studies. Conclusion. In this paper, we present novel data on vitamin D-related SNPs and response to vitamin D supplementation demonstrating the feasibility of applying functional genomic approaches in interventional studies to assess individual-level responses to vitamin D supplementation.

Vitamin D Status, Bone Mineral Density, and VDR Gene Polymorphism in a Cohort of Belarusian Postmenopausal Women

“…In the analysis of VDR gene variants distribution within groups according to vitamin D status (sufficient, insufficient, deficient), only rs731236 revealed a significant association, whereas the bearers of A/A genotypes were over-represented in the group of patients with deficiency. These data are confirmed by a recent study on response to vitamin D supplementation [ 15 ]. In haplotype analysis, which was performed to test whether combinations of different VDR gene variants may predict serum 25(OH)D concentration, the highest level of serum vitamin was found in bearers of A-T-G alleles, which are associated with PMO risk and low LS BMD.…”

“…Although several studies on different populations revealed an association of VDR gene variants with BMD [ 12 , 13 ] and serum 25(OH)D [ 14 , 15 ], many issues in this area are not fully understood. An investigation of VDR gene polymorphisms may help clarify criteria for the identification of individuals with high risk of PMO and thus conduct a timely set of preventive measures in target risk groups as well as evaluate effectiveness of therapy [ 16 ].…”

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

“…For MS, e.g., a recent meta-analysis revealed a significant association with rs731236 (TaqI) polymorphisms when comparing heterozygous (Tt) with homozygous (TT) genotypes ( 45 ). The rs731236 GG genotype was also a significant predictor of low vitamin D responsiveness in a supplementation study of 100 Arab women, together with the rs7116978 ( CYP2R1 gene) CC genotype ( 46 ). This study also provided an overview showing that the rs7116978 G allele and rs7116978 C allele reached high population prevalence of up to 40% or 70%, respectively, depending on ethnicity ( 46 ).…”

“…The rs731236 GG genotype was also a significant predictor of low vitamin D responsiveness in a supplementation study of 100 Arab women, together with the rs7116978 ( CYP2R1 gene) CC genotype ( 46 ). This study also provided an overview showing that the rs7116978 G allele and rs7116978 C allele reached high population prevalence of up to 40% or 70%, respectively, depending on ethnicity ( 46 ). It is known that certain haplotypes of VDR polymorphisms can influence its mRNA expression levels, stability and protein translation efficiency ( 47 ).…”

CYP7A1, NPC1L1, ABCB1, and CD36 Polymorphisms Are Associated with Increased Serum Coenzyme Q10 after Long-Term Supplementation in Women

“…CD36 SNPs and haplotypes are associated with serum LDL and total cholesterol levels [ 35 ]. Recently, Tomei et al reported that rs731236 in the vitamin D receptor ( VDR ) gene and rs7116978 in the cytochrome p450 family 2 subfamily R member 1 (CYP2R1 ) gene were associated with serum 25-hydroxyvitamin D levels, the primary circulating form of vitamin D, after 12 weeks of vitamin D supplementation [ 36 ]. Only a few studies have reported an association between genetic polymorphism and basal serum CoQ 10 status in humans [ 37 , 38 ] and increased serum CoQ 10 levels after the two-week supplementation [ 38 ], but there is no study reporting the association after long-term supplementation.…”