CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation

Arabi, Asma; Khoueiry-Zgheib, Nathalie; Awada, Zainab; Mahfouz, Rami; Al-Shaar, Laila; Hoteit, Maha; Rahme, Maya; Baddoura, Rafic; Halabi, George; Singh, Ravinder J.; Fuleihan, G. El Hajj

doi:10.1007/s00198-016-3713-5

Cited by 30 publications

(21 citation statements)

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“…Seasonal variations of vitamin D are well described, with lower serum 25(OH)D levels in the winter, except for countries from the Gulf states, where they are lower in the summer due to longer in-door dwelling to avoid the scorching heat. In addition, genetic factors, namely polymorphisms in key genes of the vitamin D pathway, modulate vitamin D status in western populations and possibly the Middle East ( Wang et al, 2010 ; Ahn et al, 2010 ; Arabi et al, 2017 ). The recognition of these consistent predictors justifies vitamin D supplementation strategies to prevent progression to symptomatic osteomalacia or rickets, which although becoming increasingly rare, is certainly not extinct in the region.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D in the Middle East and North Africa

et al. 2018

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PurposeThe Middle East and North Africa (MENA) region registers some of the lowest serum 25‑hydroxyvitamin D [25(OH)D] concentrations, worldwide. We describe the prevalence and the risk factors for hypovitaminosis D, completed and ongoing clinical trials, and available guidelines for vitamin D supplementation in this region.MethodsThis review is an update of previous reviews published by our group in 2013 for observational studies, and in 2015 for randomized controlled trials (RCTs) from the region. We conducted a comprehensive search in Medline, PubMed, and Embase, and the Cochrane Library, using MeSH terms and keywords relevant to vitamin D, vitamin D deficiency, and the MENA region, for the period 2012–2017 for observational studies, and 2015–2017 for RCTs. We included large cross-sectional studies with at least 100 subjects/study, and RCTs with at least 50 participants per arm.ResultsWe identified 41 observational studies. The prevalence of hypovitaminosis D, defined as a 25‑hydroxyvitamin D [25(OH)D] level below the desirable level of 20 ng/ml, ranged between 12–96% in children and adolescents, and 54–90% in pregnant women. In adults, it ranged between 44 and 96%, and the mean 25(OH)D varied between 11 and 20 ng/ml. In general, significant predictors of low 25(OH)D levels were female gender, increasing age and body mass index, veiling, winter season, use of sun screens, lower socioeconomic status, and higher latitude.We retrieved 14 RCTs comparing supplementation to control or placebo, published during the period 2015-2017: 2 in children, 8 in adults, and 4 in pregnant women. In children and adolescents, a vitamin D dose of 1000–2000 IU/d was needed to maintain serum 25(OH)D level at target. In adults and pregnant women, the increment in 25(OH)D level was inversely proportional to the dose, ranging between 0.9 and 3 ng/ml per 100 IU/d for doses ≤2000 IU/d, and between 0.1 and 0.6 ng/ml per 100 IU/d for doses ≥3000 IU/d. While the effect of vitamin D supplementation on glycemic indices is still controversial in adults, vitamin D supplementation may be protective against gestational diabetes mellitus in pregnant women. In the only identified study in the elderly, there was no significant difference between 600 IU/day and 3750 IU/day doses on bone mineral density. We did not identify any fracture studies.The available vitamin D guidelines in the region are based on expert opinion, with recommended doses between 400 and 2000 IU/d, depending on the age category, and country.ConclusionHypovitaminosis D is prevalent in the MENA region, and doses of 1000–2000 IU/d may be necessary to reach a desirable 25(OH)D level of 20 ng/ml. Studies assessing the effect of such doses of vitamin D on major outcomes, and confirming their long term safety, are needed.

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Section: Discussionmentioning

confidence: 99%

Vitamin D in the Middle East and North Africa

et al. 2018

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“…However, 25‐OH‐vitamin D3 serum levels were not significantly different between men and women probably because of small sample size with a low number of MS male. Several Authors showed that subjects carrying the AA genotype of rs10766197 CYP2R1 SNP have lower vitamin D levels compared to subjects carrying the GG genotype, after adjustment for potential predictors, including age, season and sex (Arabi et al, ; Barry et al, ).…”

Section: Discussionmentioning

confidence: 99%

Association of CYP2R1 rs10766197 with MS risk and disease progression

Scazzone

Agnello

Ragonese

et al. 2017

J of Neuroscience Research

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“…Vitamin D deficiency is characterized by bone loss, increased risk of fractures, and bone mineralization defects, which may lead to bone-related diseases such as osteoporosis, osteopenia, and osteomalacia [1][2][3][4]. Moreover, genetic variants of vitamin D3-related genes are associated with abnormal bone turnover and metabolism of bone diseases [5][6][7][8]. Vitamin D3 supplements are essential treatments for the prevention of bone loss, which underlies the mechanisms for decreasing bone resorption by osteoclasts and increasing bone formation by osteoblasts [9].…”

Section: Introductionmentioning

confidence: 99%

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts

Yoon

Lee

et al. 2020

Cells

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1α,25-dihydroxyvitamin D3 (1,25D3), the most popular drug for osteoporosis treatment, drives osteoblast differentiation and bone mineralization. Wnt/β-catenin signaling is involved in commitment and differentiation of osteoblasts, but the role of the Dickkopf-related protein 1 (DKK1), a Wnt antagonist, in osteoblasts remains unknown. Here, we demonstrate the molecular mechanism of DKK1 induction by 1,25D3 and its physiological role during osteoblast differentiation. 1,25D3 markedly promoted the expression of both CCAAT/enhancer binding protein beta (C/EBPβ) and DKK1 at day 7 during osteoblast differentiation. Interestingly, mRNA and protein levels of C/EBPβ and DKK1 in osteoblasts were elevated by 1,25D3. We also found that C/EBPβ, in response to 1,25D3, directly binds to the human DKK1 promoter. Knockdown of C/EBPβ downregulated the expression of DKK1 in osteoblasts, which was partially reversed by 1,25D3. In contrast, overexpression of C/EBPβ upregulated DKK1 expression in osteoblasts, which was enhanced by 1,25D3. Furthermore, 1,25D3 treatment in osteoblasts stimulated secretion of DKK1 protein within the endoplasmic reticulum to extracellular. Intriguingly, blocking DKK1 attenuated calcified nodule formation in mineralized osteoblasts, but not ALP activity or collagen synthesis. Taken together, these observations suggest that 1,25D3 promotes the mineralization of osteoblasts through activation of DKK1 followed by an increase of C/EBPβ.

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CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation

Abstract: This study showed a difference in 25(OH)D levels between CYP2R1 genotypes that equates a daily supplementation of 400-800 IU vitamin D, depending on genotype. It underscores possible important genetic contributions for the high prevalence of hypovitaminosis D in the Middle East.

Cited by 30 publications

References 46 publications

Vitamin D in the Middle East and North Africa

Vitamin D in the Middle East and North Africa

Association of CYP2R1 rs10766197 with MS risk and disease progression

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts

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