Elsevier

Clinical Nutrition

Volume 38, Issue 2, April 2019, Pages 676-681
Clinical Nutrition

Original article
A genetic variant in the cytochrome P450 family 2 subfamily R member 1 determines response to vitamin D supplementation

https://doi.org/10.1016/j.clnu.2018.03.018Get rights and content

Summary

Background

Globally, about 1 billion people have inadequate levels of serum vitamin D and it is prevalent in all ethnicities and age groups. Few foods naturally contain sufficient vitamin D; therefore, most people get their requirements through supplementation. Hence vitamin D status is affected by genetic and environmental determinants including season of measurement, diet habitual, health status, body mass index and concurrent medication. Further studies are necessary to understand how genetic variation influences vitamin D metabolism. We aimed to explore the association between a potential vitamin D-related polymorphism (the rs10766197 polymorphism in the CYP2R1 gene) with the response to supplementation of vitamin D in 253 healthy Iranian girls.

Material and method

A total of 253 healthy subjects received 50,000 IU of vitamin D3 weekly for 9 weeks. Serum 25(OH)D concentrations and metabolic profiles were measured at baseline and after 9 weeks of supplementation. The genotypes of the CYP2R1 variant (rs10766197) were identified using TaqMan genotyping assays.

Results

Serum 25(OH)D during the supplementation, increased in all individuals. Subjects with a AA major genotype at this locus had higher vitamin D concentrations after intervention (Changes (%) 448.4% ± 425% in AA vs 382.7% ± 301% in GG). This genetic variant modulated the response to supplementation (p < 0.001 and p-value SNP = 0.05). Regression analysis showed that the probability of affecting serum 25(OH)D, in individuals who had homozygous major allele GG was two-fold higher than carriers of the uncommon allele A (OR = 2.1 (1–4.2); p = 0.03). Interestingly, the Hs-CRP was reduced in AA carries while was elevated in individuals with GG and AG genotypes, after high-dose vitamin D supplementation.

Conclusion

Changes in serum vitamin D and metabolic profile following high dose supplementation with vitamin D were associated with CYP2R1 polymorphism. Although carriers of the common G allele showed a greater response in the serum vitamin D.

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.

References (54)

  • P.J. Albert et al.

    Vitamin D: the alternative hypothesis

    Autoimmun Rev

    (2009)
  • S.S. Khayyatzadeh et al.

    Serum transaminase concentrations and the presence of irritable bowel syndrome are associated with serum 25-hydroxy vitamin D concentrations in adolescent girls who are overweight and obese

    Ann Nutr Metabol

    (2017)
  • M. Wacker et al.

    Vitamin D—effects on skeletal and extraskeletal health and the need for supplementation

    Nutrients

    (2013)
  • M.F. Holick et al.

    Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline

    J Clin Endocrinol Metabol

    (2011)
  • H.B. Del Valle et al.

    Dietary reference intakes for calcium and vitamin D

    (2011)
  • H.A. Bischoff-Ferrari et al.

    A pooled analysis of vitamin D dose requirements for fracture prevention

    N Engl J Med

    (2012)
  • H.A. Bischoff-Ferrari et al.

    Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

    BMJ

    (2009)
  • S. Gandini et al.

    Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma

    Int J Cancer

    (2011)
  • W. Saliba et al.

    The relationship between obesity and the increase in serum 25 (OH) D levels in response to vitamin D supplementation

    Osteoporos Int

    (2013)
  • S.D. Brown et al.

    Vitamin D and asthma

    Derm Endocrinol

    (2012)
  • C.-C. Sung et al.

    Role of vitamin D in insulin resistance

    BioMed Res Int

    (2012)
  • K. Kienreich et al.

    Vitamin D and cardiovascular disease

    Nutrients

    (2013)
  • B. Weinstock-Guttman et al.

    Vitamin D and multiple sclerosis

    Neurol

    (2012)
  • S.J. Muhairi et al.

    Vitamin D deficiency among healthy adolescents in Al Ain, United Arab Emirates

    BMC Publ Health

    (2013)
  • M.F. Holick

    Vitamin D deficiency

    N Engl J Med

    (2007)
  • T.D. Thacher et al.

    Nutritional rickets around the world: causes and future directions

    Ann Trop Paediatr

    (2006)
  • T.R. Neyestani et al.

    High prevalence of vitamin D deficiency in school-age children in Tehran, 2008: a red alert

    Publ Health Nutr

    (2012)
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