Dysregulated Vitamin D, CYP2R1, TCF7L2, and CCR5 Δ32 Gene Variations are Associated with Coronary Artery Disease

Abstract

Background: Insufficient vitamin D (vit D) levels are associated with various chronic conditions such as cancers, autoimmune diseases, diabetes, and cardiovascular diseases, notably coronary artery disease (CAD). The enzyme 25-hydroxylase, cytochrome P450 2R1 (CYP2R1), catalyzes the hydroxylation of vitamin D in the liver, producing the 25-hydroxyvitamin D, which is then activated in the kidney by cytochrome P450 27B1 (CYP27B1) to form 1,25-dihydroxyvitamin D. Mutations in the CYP2R1 gene can impair vitamin D production. The C-C chemokine receptor type 5 (CCR5) supports endothelial repair and angiogenesis, with its mutation (CCR5 59029 G to A) being linked to insulin resistance and type 2 diabetes (T2D). Additionally, the transcription factor 7-like 2 (TCF7L2), part of the Wnt signaling pathway, regulates glucose homeostasis and the development of tissues, brain, liver and muscles and has been linked to obesity, insulin insensitivity, and elevated blood sugar levels.

Materials and methods: We evaluated the association of reduced serum vitamin D levels with CAD using enzyme-linked immunosorbent assay (ELISA). Genotyping of the CYP2R1 rs1562902 C > T, TCF7L2 rs12255372 G > T, and CCR5 Δ32 bp deletion mutation were performed using amplification-refractory mutation system polymerase chain reaction (PCR) and allele-specific PCR to evaluate their association with CAD risk.

Results: The CYP2R1 rs1562902 C > T single nucleotide polymorphism (SNP) genotypes CT and TT were significantly associated with CAD, with odds ratios (ORs) of 4.1 and 7.6 and p-values of 0.0001 and 0.0008, respectively. The +/Δ genotype of the CCR5 Δ32 bp (ins/del) mutation was also associated with CAD (OR = 2.51, p = 0.006). Additionally, the T allele of the TCF7L2 rs12255372 G > T SNP was linked to an increased risk of CAD (OR = 1.89, p = 0.006).

Conclusion: The CYP2R1 rs1562902 C > T, CCR5 Δ32 (rs333), and TCF7L2 rs12255372 G > T polymorphisms are potential genetic loci associated with increased CAD risk. Furthermore, CYP2R1 variants are associated with vitamin D deficiency, predisposing carriers of CYP2R1 to associated pathologies. These findings warrant further validation through larger case-control studies and functional protein analysis.

Keywords: C-C chemokine receptor type 5; amplification-refractory mutation system-PCR; coronary artery disease; cytochrome P450 2R1; transcription factor 7-like 2; vitamin D.