Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies

Abstract

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

Keywords: CYP27B1; CYP2R1; GC; VDR; autoimmune disease; vitamin D polymorphisms.

Figure 1

Functional effect of single nucleotide polymorphisms (SNPs) according to their location: (a) SNPs in promoter regions are reported to modulate gene expression by changing the conformation of the transcription factor binding site, may suppress gene expression, while others may only influence the expression of such gene; (b) SNPs in 5′ untranslated region (UTR) may modify translation initialization and transcript stabilization of messenger ribonucleic acid (mRNA); (c) SNPs in intron regions may generate splicing alteration, exon skipping, and modulate nuclear export, the rate of transcription and transcript stability; (d) SNPs in exon regions may cause the replacement of one amino acid for another, also known as non-synonymous polymorphism, which may generate a protein structure modification; (e) SNPs in 3′ UTR may modify transcript stabilization and mRNA localization in the cytoplasm. SNP: Single nucleotide polymorphism; UTR: Untranslated region; mRNA: messenger ribonucleic acid.

Figure 2

Polymorphisms in main key enzymes and proteins associated with vitamin D metabolism: localization and functional effects: (a) Vitamin D binding protein (VDBP) (encoded by GC gene) binds to ergocalciferol/cholecalciferol in order to be transported to the liver; GC (rs2282679) single nucleotide polymorphisms (SNP) due to its location in intron may generate a splicing alteration and exon skipping; (b) In the liver, 25 hydroxylase (encoded by CYP2R1 gene) converts ergocalciferol and cholecalciferol to calcidiol and then calcidiol binds to VDBP to be transported to the kidney; CYP2R1 (rs10741657)SNP located on the 5′ untranslated region (UTR) region may affect the transcript stabilization and the post-transcriptional control; (c) In the kidney, calcidiol is converted to calcitriol by the enzyme 1 alpha hydroxylase (encoded by the CYP27B1 gene); CYP27B1 (rs10877012) SNP located on 5′ UTR may affect the transcript stabilization and the post-transcriptional control of mRNA; (d) After calcitriol enters target cells and binds to vitamin D receptor (VDR) (encoded by VDR gene). Then, the VDR-calcitriol complex in the cytosol is translocated to the nucleus, where it binds to retinoid X receptor (RXR) to form a heterodimer, which interacts with vitamin D response element (VDRE) in vitamin D target genes, i.e., in T helper (Th) lymphocytes to suppress IL-17A or activate FOXP3. Mainly four SNPs have been described in the VDR gene: the FokI (rs2228570) located on exon 2, which generates a non-synonymous polymorphism with a change of C > T (also called F > f) and this results in a change of threonine to methionine. The presence of the restriction site FokI C allele (F allele), generates a new start codon (ATG) 9 bp after of the common starting site, which translate to an shorter truncated VDR protein of 424 amino acids with more transactivation capacity as a transcription factor than the wild type full-length VDR A isoform (VDRA) of 427 amino acids; the BsmI (rs1544410) located on intron 8 presents a change of A > G (also called B > b), could affect messenger ribonucleic acid (mRNA) stability and the gene expression of VDR, and also it could generate an alteration in the splice sites for mRNA transcription or a change in the intron regulatory elements of VDR; ApaI (rs7975232) located on intron 8 of VDR presents a change of A > C (also called A > a), does not change the amino acid sequence of the VDR protein, therefore could affect mRNA stability and the gene expression of VDR; TaqI (rs731236) is located on the exon 9 of VDR, presents a change of C > T (also called T > t) and generates a synonymous change of the isoleucine amino acid in the coding sequence, therefore it does not change the encoded protein, but it could influence the stability of the mRNA. All these SNPs are related to modulating de vitamin D serum status in health and disease. Ile: isoleucine; Thr: threonine; Met: methionine VDBP: vitamin D binding protein; VDR: vitamin D receptor; RXR: retinoid X receptor; VDRE: vitamin D response elements; UTR: untranslated region; THEM4: thioesterase superfamily member 4; Th: T helper lymphocyte; VDRA: wild type full-length VDR A isoform.