The impact of genetic variants related to vitamin D and autoimmunity: A systematic review

Abstract

Over the past few years, there has been a notable increment in scientific literature aimed at unraveling the genetic foundations of vitamin D signaling and its implications for susceptibility to autoimmunity, however, most of them address isolated diseases. Here, we conducted a systematic review of genetic variants related to vitamin D and autoimmune diseases and we discussed the current landscape of susceptibility and outcomes. Of 65 studies analyzed, most variants cited are in vitamin D binding protein (VDBP; rs2282679 GC gene), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the nuclear hormone receptor superfamily [FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) in VDR gene]. Therefore, our findings confirmed the associations of several genetic variants of vitamin D signaling with a broad spectrum of autoimmune diseases/traits. In addition, given the low number of papers found with functional analysis, further studies to elucidate the real effect that the variants exert on Vitamin D signaling are recommended.

Keywords: And outcomes; Autoimmune diseases; Genetic variants; Susceptibility; Vitamin D.

Graphical abstract

Fig. 1

Main genetic variants found in genes related to Vitamin D signaling and autoimmune diseases. The skin produces around 80% of Vitamin D and the remaining 20% is obtained from the diet. Cholesterol molecules are metabolized into pre-vitamin D3 through the incidence of UV rays on MC1R receptors. In blood, Vitamin D binding protein to VDBP to be transported to the liver. In the liver, the CYP27A1 and CYP2R1 enzymes catalyze the action of 25-hydroxylase in the hydroxylation of vitamin D3 to 25(OH)D3. Once again, VDBP transport Vit D metabolites. In the kidneys, the CYP27B1 enzyme is able to hydroxylate 25(OH)D3 to 1,25(OH)2D3, the active form of Vitamin D. After Vitamin D active (calcitriol) enters target cells and binds to vitamin D receptor VDR. At cellular level, VDR-calcitriol complex in the cytosol is translocated to the nucleus, where it binds to RXR, which interacts with VDRE in vitamin D target genes. Some VDREs are located within METTL1 gene. Furthermore, VDR gene is a downstream target of WT1 and may be regulated its expression. MC1R: melanocortin-1 receptor; VDBP: vitamin D binding protein; VDR: vitamin D receptor; RXR: retinoid X receptor; VDRE: vitamin D response elements.

Flowchart 1

PRISMA flow diagram.