Molecular docking study on vitamin D supplements to understand their interaction with VDR-RXRα heterodimer and VDRE of TAGAP gene.

The expression level of T cell activation Rho GTPase activating protein (TAGAP) gene is higher in rheumatoid arthritis (RA) patients compared to healthy individuals. Vitamin D receptor element (VDRE) sequences present in the regulatory region of TAGAP gene are targeted by vitamin D dependent Vitamin D receptor (VDR) - retinoic acid X receptor (RXR) heterodimer complex to regulate the TAGAP gene expression. Reduction in the expression of the TAGAP gene can prevent different severity of RA disease conditions. Calcitriol is a proven vitamin D supplement prescribed to patients with RA. However, it is involved in causing hypercalcemia. Maxacalcitol, an analog of vitamin D, is shown to have less hypercalcemic activity when compared to calcitriol. This study was done to analyze and compare the binding modes of calcitriol and maxacalcitol with VDR. We also studied the interactions of these compounds with the VDR-RXRα heterodimer complex. In addition, the binding of the ligand-activated heterodimer complexes with VDREs of the TAGAP gene was also analyzed to comprehend the binding affinities of calcitriol and maxacalcitol to the gene. The current work utilizes in silico molecular docking and simulation analysis to understand the mechanism in each complex formation.Communicated by Ramaswamy H. Sarma.

An attempt to unravel the association of TAGAP gene SNPs with rheumatoid arthritis in the Indian population using high-resolution melting analysis.

Rheumatoid arthritis (RA) is an inflammatory disease that causes inflammation of the synovium, cartilage, and deformity of the bones. Single nucleotide polymorphism (SNPs) at 5'UTR rs1738074 (A/G) and a novel candidate non-synonymous single nucleotide polymorphism (nsSNP) rs759674898 (G/A) of TAGAP gene were studied for its association with RA in the Indian population. Real-time PCR coupled with High Resolution Melting analysis technique was employed to detect SNPs. The resulting outcomes were confirmed using the "traditional" Sanger's sequencing method. From this study, we identified that rs1738074 SNP was associated with RA. The odds ratio (OR) obtained for the AG genotype was 3.3379 (Confidence Interval (C.I) 1.7881 to 6.2350); for AA genotype 0.5510 (C.I 0.3043 to 0.9979) and GG genotype 0.5609 (CI 0.3062 to 1.0275). The study also confirmed that AG heterozygous condition had more significant association with RA than AA and GG genotypes. The obtained relative risk (RR) for the AA genotype was 0.676; for AG genotype (RR = 2.253) and GG genotype (RR = 0.6741). The novel candidate nsSNP rs759674898 had only the G allele, and the A allele was not detected in the population studied. In conclusion, this study emphasizes that the rs1738074 SNP in the TAGAP gene's 5'UTR is substantially linked to RA in the Indian population.