Original articleA genetic variant in the cytochrome P450 family 2 subfamily R member 1 determines response to vitamin D supplementation
Introduction
Diet and other environmental factors such as the intake of vitamin D supplements and exposure to sunlight are known to influence serum vitamin D concentrations [1]. The assessment of serum 25-hydroxyvitamin D (25(OH)D) is the best biomarker of vitamin D status; however, the optimal serum concentration is unclear [2], [3]. A study in the United States, has suggested that a serum 25(OH)D concentration of 50 nmoL/L is sufficient for normal bone health in most individuals [4] whilst other studies have suggested that 60 nmoL/L is necessary for reduction in the risks of falling and fractures risk [5], [6]. Vitamin D has functions other than bone health. It is involved in the regulation of more than 2000 genes. Vitamin D deficiency may be associated with several non-skeletal diseases, including cancer [7], obesity [8], asthma [9], diabetes [10], cardiovascular diseases (CVD) [11] and metabolic syndrome (MS) [12] and has been reported as a major public health concern, even in regions with high levels of sunlight [13], for example it is common in the Middle East, India, Africa, Australia and South America [14], [15], [16].
In line with this, there is increasing evidence for a high prevalence of vitamin D deficiency in Iran; with reports of deficiency in >80% of the adolescence in Tehran and Arak [17], [18], about 60% of school-age girls in Yazd [19] and >70% in newborn infants in Zanjan [20]. Few foods naturally contain enough vitamin D, the most natural way to get vitamin D is cutaneous production when skin is exposed to the sunlight [3]. Public concern about the high prevalence of vitamin D deficiency has caused increasing demand for supplementation and testing. Since individual responses to supplementation is variable, a more tailored approach to supplementation may be required. The variation in serum 25(OH)D level response after supplementation has been attributed to body mass [21], baseline serum 25(OH)D level [22], supplement dose [23], and the season [22]; however, there is also convincing evidence that vitamin D status is affected by genotype [24]. Several studies have reported polymorphisms in candidate genes associated with serum vitamin D that include CYP24A1 and CYP2R1 [25], [26]. Each cytochrome P450 gene is known with CYP, implied that is part of the cytochrome P450 gene family. The common SNP, rs10766197, located in the promoter region of CYP2R1 gene, were reliable predictor of serum 25(OH)D levels [27].
The current study was carried out to examine whether treatment with high dose vitamin D supplementation is influenced by a variant in the CYP2R1 gene, using data obtained from a randomized controlled trial of vitamin D supplementation in healthy Iranian school-age girls of 12–18 years old; a group in which vitamin D deficiency is common.
Section snippets
Study population
The 253 adolescent girls were recruited between January and April 2015 in Mashhad city, using a randomized cluster sampling method. Informed consent was collected from all participants using protocols approved by the Ethics Committee of the Mashhad University of Medical Sciences.
Participants with any chronic diseases history, or who were taking any kinds of dietary supplements and anti-depressant or psychotropic drugs were excluded from study.
Individuals with history of infectious disease,
Influences of supplementation on circulation 25(OH)D in CYP2R1 variant
In the total population of 253 healthy school-age Iranian girls, 88.1% suffered from vitamin D deficiency at baseline and only 4% of the total had a desirable vitamin D level. However, after intervention, 59.7% of the subjects were at a desirable concentration of 25(OH)D. About 20.2% of the subjects remained vitamin D deficient (Fig. 1). To examine the influence of CYP2R1 variant on the circulation levels of vitamin D after intervention, subjects were categorized across rs10766197 genotype. The
Influence of supplementation on circulation 25(OH)D in CYP2R1 variant
In the present study, we explored the association of rs10766197 of the CYP2R1 vitamin D-related gene with serum 25(OH)D concentrations and found that this polymorphism was significantly associated with the serum 25(OH)D concentrations after 9 weeks of vitamin supplementation and it appeared that carriers of dominant G allele were better responder to vitamin D in respect to elevation serum vitamin D. Animal and human studies have shown that different cytochrome P450 enzymes 2(CYP) including
Conclusion
We have found that although individuals with a GG genotype of CYP2R1 variant had a greater response to vitamin D supplements, the inflammation status was worsened. However, carriers of AA genotype showed less increase in 25(OH)D than others, but inflammation status only improved in this group. We conclude that personalized advice and recommendations tailored to individual's genetics seems help to determine how different individuals with various genetic background respond to the supplementation.
Conflict of Interest
The authors have no conflict of interest to disclose.
Funding
This study was support by grants 941524 (Hamid R. Sadeghnia) from Mashhad University of Medical Sciences.
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Contributed equally as first authors.