Association of SNPs in GC and CYP2R1 with Total and Directly Measured Free 25-hydroxyvitamin D in Multi-ethnic Postmenopausal Women in Saudi Arabia(Genetic Variants in Vitamin D Metabolic Pathways in Families with Vitamin D Deficiency)

Abstract Background Group-specific component (GC) and cytochrome P450 Family 2 Subfamily R Member 1 (CYP2R1) genes are one of the vital genes involved in the vitamin D (vitD) metabolic pathway. Association of genetic polymorphisms in these two genes with 25-hyroxyvitamin D (25(OH)D) level has been reported in several studies. However, this association has been reported to be discrepant among populations from different ethnicities. Therefore, we aimed in this study to investigate association of the two major single nucleotide polymorphisms (SNP) in GC (rs4588 and rs7014) and a SNP (rs12794714) in CYP2R1 in postmenopausal women in Saudi Arabia. Methods This study randomly selected 459 postmenopausal women (aged ≥ 50 years) of multiple ethnicities in Jeddah, Saudi Arabia. Blood samples were collected from all participating women for DNA extraction and for assessment of serum levels of total 25(OH)D, directly measured free 25(OH)D and other biochemical parameters. SNPs in selected vitD related genes (rs4588 in GC, c.1364G\u003eT with transcript ID: NM_001204307.1 and rs7041 in GC, c.1353A\u003eC with transcript ID NM_001204307.1 and rs12794714 in CYP2R1, c.177G\u003eA with transcript ID NM_024514.4) were determined in DNA samples using Sanger DNA sequencing. Results Minor allele frequency for rs4588, rs7041 and rs12794714 were 0.25, 0.44 and 0.42 respectively. Genotypes of rs7041 showed significant difference in total 25(OH)D level but not in free 25(O)D level (P=0.023). In comparison, genotypes of rs4588 and rs12794714 did not show any significant difference neither in total nor in free 25(OH)D level. Post hoc test revealed that total 25(OH)D was lower in the rs7041 TT allele compared to the GG allele (P=0.022). Chi-square test showed that vitD status was associated with rs7041 genotypes (P=0.035). In addition, rs7041 minor alleles were found to have an association with vitD deficiency with a statistical significant odds ratio (\u003e1) of 2.24 and 3.51 with P=0.006 and P=0.007 for TG and GG genotypes respectively. Conclusion The rs7041 SNP in GC was associated with total 25(OH)D level in postmenopausal women in Saudi Arabia, while rs4588 in GC and rs12794714 in CYP2R1 did not show association with total 25(OH)D. Further studies exploring additional variants in vitD related genes are needed to understand genetic factors underlying vitD deficiency in Saudi population. .