SNP rs11185644 of RXRA gene is identified for dose-response variability to vitamin D3 supplementation: a randomized clinical trial

Abstract

The level of serum 25-Hydroxyvitamin D [25(OH)D] has high heritability, suggesting that genes may contribute to variations in serum 25(OH)D level and vitamin D dose-response. As vitamin D deficiency has been linked to numerous diseases, understanding how genetic variation contributes to vitamin D dose-response is important for personalized vitamin D treatment and cost-effective disease prevention. To identify genetic variants responsible for vitamin D status and dose-response, we performed two vitamin D3 and calcium clinical supplementation trials in 2,207 postmenopausal Caucasian women. We examined the association of 291 SNPs with baseline serum 25(OH)D levels and 25(OH)D dose-response. Five SNPs, rs10500804 (P = 4.93 × 10−7), rs2060793 (P = 6.63 × 10−7), rs10741657 (P = 1.49 × 10−6), rs10766197 (P = 1.05 × 10−5) and rs11023380 (P = 7.67 × 10−5) in the CYP2R1 gene, as well as 6 SNPs, rs4588 (P = 7.86 × 10−7), rs2298850 (P = 1.94 × 10−6), rs1155563 (P = 6.39 × 10−6), rs705119 (P = 2.80 × 10−5), rs705120 (P = 1.08 × 10−4) and rs222040 (P = 1.59 × 10−4) in the GC gene were associated with baseline serum 25(OH)D levels. SNP rs11185644 near the RXRA was significantly associated with 25(OH)D dose-response (P = 1.01 × 10−4). Our data suggest that polymorphisms in the CYP2R1 and GC gene may contribute to variation in baseline serum 25(OH)D concentration, and that polymorphism rs11185644 may contribute to variation in 25(OH)D dose-response in healthy postmenopausal Caucasian women.

Association of free vitamin D3 concentrations and asthma treatment failures in the VIDA Trial

“…The mechanisms underlying resistance are unknown and may be related to pharmacogenetics or genetic variants in vitamin D metabolic pathway genes, which alter the pharmacokinetics of C f vitamin D 3 . For instance, several genome-wide studies have identified loci in CYP2R1 , the gene encoding the enzyme that converts vitamin D to vitamin D 3 , and other vitamin D pathway genes that have been associated with low C tot of vitamin D 3 17,39–42 . Genetic loci in vitamin D 3 pathway genes provide a rationale as a determinant for therapeutic responsiveness to supplementation therapy and the observed inter-ethnic differences in attainable concentrations.…”

Vitamin D Supplementation and Non-Alcoholic Fatty Liver Disease: Present and Future

“…Along with baseline circulating 25(OH) vitamin D levels and dosing regimens, there are other factors which may display a critical role in determining the overall vitamin D balance and, thus, its therapeutic effects on organs and systems [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

“…In addition, genetic factors exert a significant influence on both baseline vitamin D levels and individual responses to vitamin D supplementation [ 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…Recently, Zhang M. et al [ 49 ] in an extensive study conducted on over 2200 postmenopausal women, investigated the association between 291 polymorphisms and circulating serum 25(OH) vitamin D levels before and after vitamin D and calcium supplementation and demonstrated that the vitamin D-related CYP2R1 and GC genes—the latter encoding for Vitamin D-binding protein, VDBP—contribute to the variability of baseline vitamin D concentration, whereas the rs11185644 polymorphism, sited near the retinoid X receptor α (RXR α) gene, influences 25(OH) vitamin D dose–response variations independently of age, body mass index (BMI) and seasonality [ 49 ].…”

“…VDBP is the main vitamin D carrier protein, binding 85 to 90% of total circulating 25(OH) vitamin D, and inhibits some vitamin D action since the bound fraction may be unavailable to act on target cells [ 52 ]. Thus, genotyping studies demonstrated that two VDBP polymorphisms—rs4588 and rs7041—highly prevalent in general population and associated with the race, are not only associated with serum 25(OH) vitamin D levels [ 49 , 50 ] but also explain almost 80% of circulating VDBP inter-individual variation. Therefore, by reducing both VDBP and 25(OH) vitamin D, VDBP-associated SNPs may justify equal vitamin D availability and action in different ethnic groups, independent of measured 25(OH) vitamin D concentration [ 50 ].…”