Interaction Between Vitamin D Metabolism Genetic Variants: Association with Hypovitaminosis D, Rheumatoid Arthritis, and Its Clinical Disease Activity

Abstract

Background: Hypovitaminosis D has been associated with worse rheumatoid arthritis (RA) manifestations. Notably, different genetic studies have reported that approximately 65% of hypovitaminosis D can be partially explained using the presence of single-nucleotide variants (SNVs) in key genes involved in its metabolism. This study aimed to investigate the association and gene-gene interactions of four SNVs in vitamin D metabolism genes, rs10741657 (CYP2R1), rs10877012 (CYP27B1), rs4809959 (CYP24A1), and rs731236 TaqI (VDR), with hypovitaminosis D, RA, and its clinical disease activity in a Mexican mestizo population.

Methods: This study was conducted among females: 204 RA patients and 204 control subjects (CS). Vitamin D serum levels (calcidiol) were analyzed using ELISA, SNVs through allelic discrimination with TaqMan^® probes, and were analyzed using a multifactor dimensionality reduction (MDR) method.

Results: MDR analysis suggested that GG and TT genotypes of rs10877012 (CYP27B1) were linked to lower calcidiol levels, while the CT and CC genotypes of rs731236 TaqI (VDR) were associated with increased RA susceptibility and higher disease activity. Logistic regression confirmed that the GG genotype of rs10877012 (CYP27B1) was associated with hypovitaminosis D (OR = 1.8; CI: 1.1-3.0; p = 0.01), and the CT genotype of rs731236 TaqI (VDR) with RA (OR = 1.9; CI: 1.2-2.9; p < 0.01) and high DAS28-ESR (OR = 3.6; CI: 1.3-10.7; p < 0.01).

Conclusions: The GG genotype of rs10877012 CYP27B1 was associated with susceptibility to hypovitaminosis D, whereas the CT genotype of rs731236 TaqI VDR confers susceptibility to RA and high clinical disease activity in the Mexican mestizo population.

Keywords: CYP27B1; genetic variants; hypovitaminosis D; multifactor dimensionality reduction (MDR); rheumatoid arthritis; vitamin D; vitamin D genes; vitamin D receptor.

Figure 1

Three-locus interaction of variants in vitamin D metabolism genes for hypovitaminosis D, RA, and its clinical disease activity susceptibility. (a) Susceptibility to hypovitaminosis D. Deficiency cases (left bar) and non-deficiency cases (right bar). (b) Susceptibility to RA. RA cases (left bar) and CS (right bar). (c) Susceptibility to RA clinical activity. Active disease (left bar) and remission (right bar). Multifactor Dimensionality Reduction (MDR) analysis. Each panel represents the interaction between combinations of SNVs in genes involved in vitamin D metabolism: rs10741657 in CYP2R1, rs4809959 in CYP24A1, rs10877012 in CYP27B1, and rs731236 TaqI in VDR. Left bars in each cell represent the percentage of RA patients; right bars represent CS. Cells shaded in dark gray and light gray denote genotype combinations classified as high-susceptibility and low susceptibility, respectively, based on the ratio of RA patients to CS. Blank cells indicate that genotype combinations are not present in the data.