Investigating the Association of Vitamin D Metabolism Genes CYP2R1, CYP24A1 and CYP27B1 with Vitamin...

Fatme Al Anouti, Sarah El Hajj Chehadeh, Enas Osman, Gehad ElGhazali, Habiba Al Safar

Journal of Food and Nutrition Research

Investigating the Association of Vitamin D Metabolism Genes CYP2R1, CYP24A1 and CYP27B1 with Vitamin D Status in Young Adult Emiratis

Fatme Al Anouti1, Sarah El Hajj Chehadeh2, Enas Osman2, Gehad ElGhazali3, Habiba Al Safar2, 4,

1Zayed University, Abu Dhabi, United Arab Emirates

2Khalifa University Center of Biotechnology, Abu Dhabi, United Arab emirates

3Institute of Laboratory Medicine, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates

4Khalifa University of Science, Technology & Research, Biomedical Department, Abu Dhabi, United Arab Emirates

Abstract

Despite the sunny weather in the Arabic Gulf Countries, vitamin D (VTD) insufficiency has been recently recognized as a serious health problem in this region. While diet and sun exposure are the main factors which determine the concentration of 25-hydroxyvitamin D3 [25(OH)D3], genetic variants VTD metabolizing enzymes, especially CYP2R1, CYP24A1 and CYP27B1, have gained a lot of interest lately. This study aims to investigate the association between VTD insufficiency and genetic variants of CYP2R1, CYP27B1 and CYP24A1 among young adult Emiratis. Healthy young adult United Arab Emirates (UAE) nationals (111 female, 52 male) with a mean age of 20.32 ± 2.35 years were recruited for the study. Genotyping for 5 single nucleotide polymorphisms (SNPs) in CYP2R1, CYP24A1 and CYP27B1 genes were performed by TaqMan® assays, while serum 25(OH)D3 was measured by Diasorin analyzer (LIAISON). Our results showed that the GT+TT genotype of CYP27B1 (rs10877012) (OR: 6.13, 95%CI [1.76-21.33], p=0.001) and the AG+GG genotype of CYP27B1 (rs4646536) (OR: 2.57, 95%CI [1.02-6.49], p=0.040) were significantly more frequent in VTD insufficient subjects while the GG genotype of CYP24A1 (rs2762939) (OR: 0.10, 95%CI [0.006-1.81], p=0.036) and the TT genotype of CYP24A1 (rs6013897) (OR: 0.10, 95%CI [0.006-1.76], p=0.033) were significantly more frequent in sufficient subjects. Moreover, the haplotype (GTGA) was significantly more frequent in sufficient subjects (p=1.22x10-5), while the frequency of haplotype GTTG was significantly high in the insufficient group (p=0.004). The data strongly suggest that genetic variants relevant to VTD metabolism could play an important role in defining VTD status among the young adult Emirati population.

Cite this article:

  • Fatme Al Anouti, Sarah El Hajj Chehadeh, Enas Osman, Gehad ElGhazali, Habiba Al Safar. Investigating the Association of Vitamin D Metabolism Genes CYP2R1, CYP24A1 and CYP27B1 with Vitamin D Status in Young Adult Emiratis. Journal of Food and Nutrition Research. Vol. 5, No. 1, 2017, pp 15-21. http://pubs.sciepub.com/jfnr/5/1/3
  • Anouti, Fatme Al, et al. "Investigating the Association of Vitamin D Metabolism Genes CYP2R1, CYP24A1 and CYP27B1 with Vitamin D Status in Young Adult Emiratis." Journal of Food and Nutrition Research 5.1 (2017): 15-21.
  • Anouti, F. A. , Chehadeh, S. E. H. , Osman, E. , ElGhazali, G. , & Safar, H. A. (2017). Investigating the Association of Vitamin D Metabolism Genes CYP2R1, CYP24A1 and CYP27B1 with Vitamin D Status in Young Adult Emiratis. Journal of Food and Nutrition Research, 5(1), 15-21.
  • Anouti, Fatme Al, Sarah El Hajj Chehadeh, Enas Osman, Gehad ElGhazali, and Habiba Al Safar. "Investigating the Association of Vitamin D Metabolism Genes CYP2R1, CYP24A1 and CYP27B1 with Vitamin D Status in Young Adult Emiratis." Journal of Food and Nutrition Research 5, no. 1 (2017): 15-21.

Import into BibTeX Import into EndNote Import into RefMan Import into RefWorks

1. Introduction

The recent VTD insufficiency pandemic has been influencing people of all age groups across different countries. Studies among U.S population demonstrated that more than 70% of children and around 77% of adults have insufficient VTD status with race ethnic differences [1, 2]. Several research investigations have revealed that VTD insufficiency is associated with higher risk of cardiovascular mortality [3], cancer incidence [4], and autoimmune diseases like multiple sclerosis [5].

Although the body can normally secure its adequate VTD requirement by directly exposing skin to sunlight and consuming VTD rich/enriched foods, the VTD obtained from such sources is inactive and needs further activation within the body before achieving full hormonal function. Metabolic activation of VTD requires two hydroxylation steps, the first of which occurs in the liver and the second in the kidney. Following the metabolic action of hepatic and renal enzymes, the active hormone, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, calcitriol] is produced. Inadequate sunlight exposure and intake of dietary VTD, liver or kidney diseases can significantly reduce the level of active VTD and hence increase the risk of VTD insufficiency [6].

VTD metabolism is complex and involves several key enzymes which might alter the status of VTD. This includes 25-hydroxylase (CYP2R1), a hepatic enzyme which converts VTD3 to 25-hydroxyvitamin D3 [25(OH)D3, Calcifediol] [7], another essential enzyme is 1-hydroxylase (CYP27B1), which is found mainly in the kidneys, and converts Calcifediol to calcitriol the bioactive form of vitamin D3, by hdroxylating 25(OH)D3 into 1,25(OH)2D3. The last key enzyme is 24-hydroxylase (CYP24A1), that regulates the level of 1,25(OH)2D3 via hydroxylation at C24 which results in a sensational diminishing in the biological activities of VTD, prompts further oxidation to produce calcitroic acid which is passed in the urine [8].

Researchers identified SNPs that are associated with the modification of 25(OH)D3 level in response to VTD supplementation; two SNPs in CYP24A1 (rs2209314 and rs2762939), one SNP rs10766197 in CYP2R1, another rs6013897 in CYP24A1 and rs7968585 in VDR are well represented in several populations [7]. Several studies have shown that the Gulf region has one of the highest rates of VTD insufficiency and deficiency around the globe, paradoxically despite the abundance of sunlight throughout the entire year [9]. According to recent study, 63.2% of UAE residents who work indoors (N=141) suffer from VTD deficiency due to the sun avoidance behaviors [10]. A current study conducted at a hospital in Dubai (UAE) reviewed the medical records of 2,736 patients between 2008 and 2012. All individuals examined were not taking VTD supplements upon first visit and it was found that 81.9 % suffered from VTD insufficiency. Three quarters of these patients were UAE nationals [11]. Another study conducted in Al Ain, (UAE), illustrated that 45.4% of adolescents (N=315) were VTD insufficient [12]. Additionally, a recent study at Zayed University in Abu-Dhabi (UAE) tested a random sample of 138 females and 70 males for serum 25(OH)D3 levels. The mean concentrations for serum 25(OH)D3 for females and males were 20.9 ± 14.9 nmol/L and 27.3 ± 15.7 nmol/L, respectively and were below the adequacy threshold [13].

Recently, genetic polymorphism of VTD metabolizing enzymes has gained interest because of the association of VTD metabolism with T2DM, CVDs and many other chronic illnesses [14]. Therefore this study aimed to examine the association of genetic polymorphism between VTD insufficiency and the metabolizing enzymes; CYP2R1, CYP27B1 and CYP24A1 among a representative sample of Emirati Youth.

2. Materials and Methods

2.1. Study Area and Participants

A total of 163 unrelated healthy UAE national students (111 female and 52 male) were recruited for the study at Khalifa University of Science, Technology and Research (KUSTAR) from November 2014 to November 2015. Registered nurses from Burjeel/VPS healthcare hospital in Abu Dhabi collected samples. The ethical review committee of KUSTAR and Burjeel/VPS healthcare hospital approved the study. The subjects were informed about the study and signed an informed written consent prior to participation. Each participant filled out a validated questionnaire that provided the needed information that could play a role in the predisposition to VTD insufficiency which includes lifestyle and environmental factors.

2.2. Study Design and Definitions

Based on serum 25(OH)D3 levels, the participants were categorized into either VTD sufficient or insufficient. VTD insufficiency was defined as serum 25(OH)D3 level ≤50nmol/l while VTD sufficiency was defined as serum 25(OH)D3 level >50nmol/l [15]. Individual with Vitamin D supplementation were excluded from this study. Body Mass Index (BMI) was determined and recorded for all the subjects using the Standard BMI formula, as body weight (kg) divided by height (m) squared. Individuals with a BMI score of greater than or equal to 30 were considered to be ‘obese’ and those with a BMI greater than or equal to 25 were grouped into the overweight group [16].

Allele, genotype and haplotype frequencies of 5 SNPs in 3 enzymes involved in VTD metabolism, CYP27B1 (rs10877012; rs4646536), CYP24A1 (rs2762939; rs6013897) and CYP2R1 (rs10741657) were compared between participants with VTD levels >50nmol/l (sufficient) and those with levels ≤50nmol/l (insufficient).

2.3. Blood Sampling

Four ml of blood was collected from each subject using anti-coagulant tubes (BD Vacutainer ®, Franklin Lakes, New Jersey, USA). Samples were aliquoted equally into two tubes, one for measuring serum 25(OH)D3 as an indicator for VTD level in the body by DiaSorin (LIAISON ®, Saluggia, Italy) [17] and another for DNA extraction [18]. DNA from all samples was extracted within 48 hours.

2.4. DNA Extraction, SNP Selection and Genotyping

Genomic DNA was extracted from blood samples using QIAamp DNA Mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. DNA was quantified using NanoDrop 2000c UV-Vis spectrophotometer (Thermo scientific, USA). DNA samples were diluted to 10 ng/µL and frozen for subsequent PCR reactions. Five SNPs in VTD metabolism genes were selected CYP24A1 (rs2762939, rs6013897), CYP27B1 (rs4646536, rs10877012) and CYP2R1 (rs10741657) for genotyping. This selection was based on data from population-based studies that revealed the association of specific SNPs with VTD status [19-24][19]. Genotyping was performed using TaqMan® real-Time PCR assays (Applied Biosystems, Foster City, CA) [18]. PCR amplification reactions were carried out in 96 well plates (Applied Biosystems) by using the ViiA™ 7 Real-Time PCR System (Applied Biosystems). Each reaction was performed according to the manufacturer’s instructions with a final reaction volume of 10 μl that contained 10 ng of genomic DNA, 5 μl of TaqMan GTXpress Master Mix (Applied Biosystems) and 0.5 μl of primers and probes (20X). Primer and TaqMan® minor groove binding group (MGB) probe (FAM and VIC® dye-labeled) sets used for TaqMan real-Time PCR. Amplification reactions began with incubation at 95°C for 20s and was followed by 40 cycles of 95°C for 3s (denaturing) and 60°C for 20s (annealing/extension). Result assessment of the SNPs’ amplifications and genotyping was carried out using the ViiA™ 7 Software (Applied Biosystems). Samples were run in duplicates, with positive, negative controls and blanks. SNPs call rate was 99.65%.

2.5. Data Analysis

For determining the sample size, we utilized the Power Calculator for Genetic Studies developed by Skol and his team (http://www.sph.umich.edu/csg/abecasis/CaTS/index.html). Using VTD prevalence rate of 20% in the adult population of United Arab Emirates as reported by Muhairi et al., 2013 [12]. The major allele frequencies of ≥ 0.50 were predicted, and a multiplicative disease model was assumed. From the power calculator: 100-250 controls were needed for this study to be able to reject the null hypothesis with an OR of ≥ 1.5 reaching at least 85% power.

The data was analyzed using the statistical program Stata version 13 (StataCorp. College Station, Texas, USA). The results for continuous variables were expressed as mean ± SE and as percentages for categorical variables. The Hardy-Weinberg equilibrium at individual loci was assessed by χ2 test using de Finetti program (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). The categorical variables in Table 1 were tested by χ2 test and the continuous variables by Fisher’s exact test. A χ2 test was used to compare the genotype and allele frequencies for each SNP between insufficient and sufficient groups. Allele frequency was calculated as the number of occurrences of the test allele in the population divided by the total number of alleles. All p values were two sided, and differences were considered statistically significant for p< 0.05. Odds ratio (OR) were set at 95% confidence interval (CI). The SHEsis online haplotype analysis software (http://analysis.bio-x.cn/myAnalysis.php) was used to test the haplotypes.

3. Results

The study population consisted of a total of 163 participants (111 female, 52 male) as a representative sample of the young adult Emiratis within Khalifa University. The mean ± SE age of the VTD insufficient group (n=136) was 19.72 ± 0.19 years while the mean age of the sufficient group (n=27) was 20.15 ± 0.55 years. The characteristics of the healthy unrelated Emirati subjects were summarized in Table 1. Mean ± SE serum 25(OH)D3 concentration was 71.92 ± 4.43 nmol/l in sufficient group and significantly lower in insufficient group (26.23 ± 0.97; p=0.00001). Compared to the sufficient group, the insufficient subjects were less physically active (p=0.023).

Table 1. General characteristics of healthy unrelated Emirati subjects enrolled in the study

Table 2 presents the correlation between five different SNPs in CYP2R1, CYP24A1 and CYP27B1 genes and serum 25(OH)D3 levels. None of the genotype distributions for the SNPs showed deviations from Hardy-Weinberg Equilibrium proportions. Our results indicated that some genotypes of the VTD metabolizing enzymes were significantly more frequent among VTD insufficient subjects, such as the GT+TT genotype of CYP27B1 (rs10877012) (OR: 6.13, 95% CI [1.76-21.33], p=0.001) and the AG+GG genotype of CYP27B11 (rs4646536) (OR: 2.57, 95% CI [1.02-6.49], p=0.040), while on the other hand the GG genotype of CYP24A1 (rs2762939) (OR: 0.10, 95% CI [0.006-1.81], p=0.036) and the TT genotype of CYP24A1 (rs6013897) (OR: 0.10, 95% CI [0.006-1.76], p=0.033) were significantly more frequent among VTD sufficient subjects. No significant association was found between the genetic variant in CYP2R1 and the status of VTD among the studied Emirati subpopulation.

Table 2. Genotype and allele frequencies of the CYP24A1, CYP27B1 and CYP2R1 SNPs in the context of serum 25(OH)D3 levels

Table 3. Haplotype frequency in CYP24A1 and CYP27B1 in the context of serum 25(OH)D3 levels

Table 3 depicts haplotype frequencies of the 4 SNPs in CYP24A1 and CYP27B1 and demonstrates that almost all haplotypes from SNPs rs2762393, rs6013897 in CYP24A1 and rs10877012, rs4646536 in CYP27B1 were predominant among VTD insufficient young adult Emirati participants. The haplotype with the four alleles GTGA (rs2762393, rs6013897, rs10877012, rs4646536) exhibited the highest frequency of 69.9% among the sufficient group (OR: 0.23, 95% CI 0.11-0.46], p=1.22x10-5), while the GTTG haplotype was more frequent in the insufficient group (p=0.004).

In addition, comparing the BMI values among sufficient and insufficient participant mean BMI was 23.77 ± 0.47 in the insufficient group and 23.29 ± 0.92 in the sufficient group.

4. Discussion

Recent studies revealed that several polymorphisms of VTD metabolism genes have been linked to T2DM, CVDs, cancer and other chronic illnesses [25]. However, conflicting results have been reported regarding the association of the genetic variants of VTD metabolism genes in different ethnic groups.

There are three known cytochrome P450s (CYPs) and possibly other VTD-related CYPs linked to the metabolism of VTD. The major enzymes in VTD metabolism are the hepatic 25-hydroxylase (CYP2R1), renal 25-hydroxyvitamin D-1a-hydroxylase (CYP27B1), and 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) [26].

Studies of genetic variants that specifically affect 25(OH)D3 concentrations can provide another route to interpret the underlying cause of VTD insufficiency. Therefore in the present prospective study, we examined the association of genetic polymorphism of the metabolizing enzymes; CYP2R1, CYP27B1 and CYP24A1 with VTD status among a representative sample of young adult Emiratis. Specifically, we have investigated five SNPs; rs2762939, rs6013897 in CYP24A1, rs4646536, rs10877012 in CYP27B1and rs10741657 in CYP2R1.

CYP2R1 is a liver enzyme that catalyzes the hydroxylation of VTD3 to its active form, 25(OH)D3. Cheng et al., 2003 identified a polymorphism in CYP2R1 which was found to be associated with VTD metabolism [27]. The rs10741657 variant located in the promoter region of the CYP2R1 gene affects the enzymatic activity of CYP2R1 and cause a relative lack of 25(OH)D3 [28]. However, our results showed no association between rs10741657 variant and the lower VTD levels in young adult Emirati subpopulation. There was no significant difference between the allele and genotype frequencies of rs10741657 in (CYP2R1) in both sufficient and insufficient subgroups.

CYP24A1 is the cytochrome P450 component of the 25-hydroxyvitamin D-24-hydroxylase enzyme that catalyzes the conversion of 25(OH)D3 and 1,25(OH)2D3 into the less active 24-hydroxylated products, which lead to inadequate VTD status due to degradation of active VTD [29]. This had been linked to obesity one of the significant parameters of Type 2 Diabetes [30]. A common variant in CYP24A1, is associated with obesity and its related phenotypes in Chinese Han population [31]. The rs2762939 variant located in intron 5 and the rs6013897 located in the intergenic region downstream of CYP24A1, were associated with high 25(OH)D3 levels. In our, the mutant alleles G (rs2762939) and T (rs6013897) of CYP24A1 were significantly more frequent in VTD sufficient group than the insufficient. Based on such results, we can conclude that two variants of CYP24A1 were associated with reduced risk of VTD insufficiency among young adult Emiratis. This result was in concordance with another study conducted in western New York which reported an association between rs2762939 (CYP24A1) and reduced risk of VTD insufficiency among colorectal cancer patients [21].

An association between reduced 25(OH)D3 levels and rs10877012 in CYP27B1 promoter polymorphism leading to reduced 1,25(OH)2D3 levels among the British population [32, 33] has been reported in literature. Our results support this finding, as rs10877012 was associated with increased risk of VTD insufficiency. Specifically the GT+TT genotype of rs10877012 and the AG+GG genotype of rs4646536 were significantly more frequent in VTD insufficient subjects. The data strongly indicates that genetic variants relevant to VTD metabolism could play an important role in defining VTD status among the young adult Emiratis. CYP27B1 also known as 1α-hydroxylase is the enzyme responsible for the hydroxylation of 25(OH)D3 to form 1,25(OH)2D3. This enzyme carries out the final reaction to convert VTD to its active form, 1,25(OH)2D3 in the kidneys [13]. The two variant that we have studied here, rs10877012 in the 5’region and rs4646536 in intron 6, reduce the activity of CYP27B1 leading to decreased the level of 1,25(OH)2D3 [33]. Thus, even if subjects who carry this genotype receive a sufficient amount of sun exposure, they would still suffer from VTD insufficiency because of inefficient conversion of VTD into the active form. The inconvenience of measuring serum 1,25(OH)2D3 levels adds more emphasis on the need to screen for such risk genotypes and to identify individuals properly so as to tailor supplementation therapy.

Furthermore, our results indicated that the haplotype of four SNPs rs2762939, rs6013897 in CYP24A1 and rs10877012, rs4646536 in CYP27B1 could be associated with lower VTD levels. Specifically, the haplotype carrying G allele from rs2762393 and T from rs6013897 in CYP24A1 and T allele from rs10877012 and G allele from rs4646536 in CYP27B1 are more frequent in insufficient subjects. This could have important implications for predicting the VTD status and further direct prognosis for a number of clinically significant diseases such as cancer and T2D in subjects with these haplotypes.

Therefore, in light of these associations, it is feasible to conclude that the optimal concentration of 25(OH)D3 in the body is correlated to CYP24A1 and CYP27B1 genotype. Future work will include measuring 1,25(OH)2D3 in patients along with 25(OH)D3 to strengthen our results.

In conclusion, this unique study illustrated the association between genetic variants at the VTD metabolism sites and VTD insufficiency among young adult Emiratis. We have determined the frequency of CYP2R1, CYP24A1 and CYP27B1 polymorphism in young Emirati subpopulation. In addition, the highest haplotype frequency of CYP24A1 and CYP27B1 was presented by the GTGA haplotype and this indicates that individuals with a haplotype of GTGA are highly to be VTD sufficient. Therefore, this study shed light on a serious public health issue that should definitely get much more attention in the Gulf region and correlated the genotype of VTD metabolism genes with the level of serum 25(OH)D3.

Therefore, this study shed light on a serious public health issue that should definitely get much more attention in the Gulf region and correlated the genotype of VTD metabolism genes with the level of serum 25(OH)D3. Further research investigations need to be conducted to identify any link between specific VTD metabolism gene haplotypes and chronic diseases.

List of Abbreviations

1,25(OH)2D3: 1,25-dihydroxyvitamin D3

25(OH)D3: 25-hydroxyvitamin D3

95% CI: 95% confidence interval

BMI: Body Mass Index

CVDs: Cardiovascular diseases

CYPs: cytochrome P450s

KUSTAR: Khalifa University of Science, Technology and Research

OR: Odds ratio

SNPs: Single nucleotide polymorphisms

T2DM: Type 2 Diabetes Mellitus

UAE: United Arab Emirates

VTD: Vitamin D

Statement of Competing Interests

All the authors declare no conflict of interest.

Acknowledgments

We gratefully acknowledge the contribution of participating individuals members whose cooperation made this study possible. This study was supported by research incentive funds from Zayed University granted to F. Al Anouti.

Author Contribution

Drs. Alsafar, and Al Anouti have designed the study, prepared the manuscript and performed all the data analyses with assistance from co-authors. Specifically, Ms Sarah El Hajj Chehadeh has performed all laboratory work in Molecular Cell Biology laboratory at Khalifa University Biotechnology center. Drs El Ghazali provided endless support by contributing to the design and discussion of this study.

References

[1]  Bandeira F, Griz L, Dreyer P, Eufrazino C, Bandeira C, et al. (2006). Vitamin D deficiency: a global perspective. Arquivos Brasileiros de Endocrinologia & Metabologia 50: 640-646.
In article      View Article  PubMed
 
[2]  Gordon NP, Caan BJ, Asgari MM (2012). Variation in vitamin D supplementation among adults in a multi-race/ethnic health plan population, 2008. Nutrition journal 11: 1.
In article      View Article  PubMed
 
[3]  Pilz S, Tomaschitz A, März W, Drechsler C, Ritz E, et al. (2011). Vitamin D, cardiovascular disease and mortality. Clinical endocrinology 75: 575-584.
In article      View Article
 
[4]  Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, et al. (2011). Meta‐analysis of observational studies of serum 25‐hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. International Journal of Cancer 128: 1414-1424.
In article      View Article  PubMed
 
[5]  Weinstock-Guttman B, Mehta BK, Ramanathan M, Karmon Y, Henson LJ, et al. (2012). Vitamin D and multiple sclerosis. The neurologist 18: 179-183.
In article      View Article  PubMed
 
[6]  Dawodu A, Absood G, Patel M, Agarwal M, Ezimokhai M, et al. (1998). Biosocial factors affecting vitamin D status of women of childbearing age in the United Arab Emirates. Journal of biosocial science 30: 431-437.
In article      View Article  PubMed
 
[7]  Barry EL, Rees JR, Peacock JL, Mott LA, Amos CI, et al. (2014). Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. The Journal of Clinical Endocrinology & Metabolism 99: E2133-E2137.
In article      View Article  PubMed
 
[8]  Sakaki T, Kagawa N, Yamamoto K, Inouye K (2005). Metabolism of vitamin D3 by cytochromes P450. Front Biosci 10.
In article      
 
[9]  Badawi A, Arora P, Sadoun E, Al-Thani A-A, Al Thani MH (2012). Prevalence of vitamin D insufficiency in Qatar: a systematic review. Journal of public health research 1: 229-235.
In article      View Article  PubMed
 
[10]  Al-Anouti F, Al-Ameri S, Thomas J, Abdel-Wareth L, Devkaran S, et al. (2013). Sun avoidance among indoor employees leading to vitamin D deficiency and depression in the United Arab Emirates. International Journal of Medicine and Medical Sciences 5: 503-509.
In article      
 
[11]  Abdelgadir EIE, Bashier AM, Kathamuthu R, Bashiri S, Alawadi F (2013) Vitamin D Deficiency and Insufficiency in Patients Attending a General Hospital in Dubai, United Arab Emirates. Ibnosina Journal of Medicine and Biomedical Sciences 6: 81-84.
In article      
 
[12]  Muhairi SJ, Mehairi AE, Khouri AA, Naqbi MM, Maskari FA, et al. (2013). Vitamin D deficiency among healthy adolescents in Al Ain, United Arab Emirates. BMC Public Health 13: 1.
In article      View Article  PubMed
 
[13]  Al Anouti F, Thomas J, Abdel-Wareth L, Rajah J, Grant WB, et al. (2011). Vitamin D deficiency and sun avoidance among university students at Abu Dhabi, United Arab Emirates. Dermato-endocrinology 3: 235-239.
In article      View Article  PubMed
 
[14]  Autier P, Gandini S (2007). Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Archives of internal medicine 167: 1730-1737.
In article      View Article  PubMed
 
[15]  Ross A, Taylor C, Yaktine A, Del Valle H (2011). Dietary reference intakes for vitamin D and calcium. Food and nutrition 4th ed Washington DC: The national academies press.
In article      
 
[16]  (January 2015). World Health Organisation. Obesity and overweight http://wwwwhoint/mediacentre/factsheets/fs311/en/.
In article      
 
[17]  Ersfeld DL, Rao DS, Body J-J, Sackrison JL, Miller AB, et al. (2004). Analytical and clinical validation of the 25 OH vitamin D assay for the LIAISON® automated analyzer. Clinical biochemistry 37: 867-874.
In article      View Article  PubMed
 
[18]  Osman E, Al Anouti F, Haq A, Mirgani R, Al Safar H (2015). Frequency of rs731236 (Taql), rs2228570 (Fok1) of Vitamin-D Receptor (VDR) gene in Emirati healthy population. Meta gene 6: 49-52.
In article      View Article  PubMed
 
[19]  Gilbert R, Bonilla C, Metcalfe C, Lewis S, Evans DM, et al. (2015). Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1, 25-dihydroxyvitamin-D, and prostate cancer: a nested case–control study. Cancer Causes & Control 26: 205-218.
In article      View Article  PubMed
 
[20]  Hibler EA, Klimentidis YC, Jurutka PW, Kohler LN, Lance P, et al. (2015). CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence. Nutrition and cancer 67: 1131-1141.
In article      View Article  PubMed
 
[21]  Muindi JR, Adjei AA, Wu ZR, Olson I, Huang H, et al. (2013). Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: correlation with polymorphisms in the vitamin D genes. Hormones and Cancer 4: 242-250.
In article      View Article  PubMed
 
[22]  Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, et al. (2011). Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60: 1624-1631.
In article      View Article  PubMed
 
[23]  McGrath JJ, Saha S, Burne TH, Eyles DW (2010). A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations. The Journal of steroid biochemistry and molecular biology 121: 471-477.
In article      View Article  PubMed
 
[24]  Orton S-M, Morris AP, Herrera BM, Ramagopalan SV, Lincoln MR, et al. (2008). Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. The American journal of clinical nutrition 88: 441-447.
In article      PubMed  PubMed
 
[25]  Kong J, Xu F, Qu J, Wang Y, Gao M, et al. (2015). Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival. Oncotarget 6: 2573-2582.
In article      View Article  PubMed
 
[26]  Masuda S, Byford V, Arabian A, Sakai Y, Demay MB, et al. (2005). Altered pharmacokinetics of 1α, 25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 in the blood and tissues of the 25-hydroxyvitamin D-24-hydroxylase (Cyp24a1) null mouse. Endocrinology 146: 825-834.
In article      View Article  PubMed
 
[27]  Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003). De-orphanization of Cytochrome P450 2R1 a microsomal vitamin D 25-hydroxylase. Journal of Biological Chemistry 278: 38084-38093.
In article      View Article  PubMed
 
[28]  Bu F-X, Armas L, Lappe J, Zhou Y, Gao G, et al. (2010). Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Human genetics 128: 549-556.
In article      View Article  PubMed
 
[29]  Veldurthy V, Wei R, Campbell M, Lupicki K, Dhawan P, et al. (2016). 25-Hydroxyvitamin D 3 24-Hydroxylase: A Key Regulator of 1, 25 (OH) 2 D 3 Catabolism and Calcium Homeostasis. Vitamins & Hormones 100: 137-150.
In article      View Article  PubMed
 
[30]  Kuroda M, Sakaue H (2016). [Role of vitamin D and calcium in obesity and type 2 diabetes]. Clin Calcium 26: 349-354.
In article      PubMed
 
[31]  Lu L, Gan W, Zhu J, Tang H, Li H, et al. (2012). Associations between common variants in CYP24A1 and risk of obesity in Chinese Hans. The FASEB Journal 26: 386.381.
In article      
 
[32]  Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, et al. (2011). Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. Journal of hepatology 54: 887-893.
In article      View Article  PubMed
 
[33]  Bailey R, Cooper JD, Zeitels L, Smyth DJ, Yang JH, et al. (2007). Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes. Diabetes 56: 2616-2621.
In article      View Article  PubMed
 
  • CiteULikeCiteULike
  • MendeleyMendeley
  • StumbleUponStumbleUpon
  • Add to DeliciousDelicious
  • FacebookFacebook
  • TwitterTwitter
  • LinkedInLinkedIn