The multiple sclerosis-associated regulatory variant rs10877013 affects expression of <i>CYP27B1</i> and <i>VDR</i> under inflammatory or vitamin D stimuli

Karaky, Mohamad; Alcina, Antonio; Fedetz, Marı́a; Barrionuevo, Cristina; Potenciano, Victor; Delgado, Concepción; Izquierdo, Guillermo; Matesanz, Fuencisla

doi:10.1177/1352458515610208

Cited by 19 publications

(10 citation statements)

References 35 publications

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“…In these studies, disease-associated SNPs have been identified in an extended region that contains the CYP27B1 gene as well as neighboring genes that include METTL1 and METTL21B (FAM119B) (56,57). Indeed, some genotypes appear to be preferential for the altered expression of CYP27B1, although observed co-regulation of the METTL21B gene has introduced some complexity.…”

Section: Endocrine Regulation Of Cyp27b1mentioning

confidence: 99%

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

Meyer

Benkusky

Kaufmann

et al. 2017

Journal of Biological Chemistry

127

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The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D 3 to its hormonal form, 1␣,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH) 2 D 3 -mediated regulation of Cyp27b1 expression. Selective genomic deletion of key components within this module in mice resulted in loss of either PTH induction or FGF23 and 1,25(OH) 2 D 3 suppression of Cyp27b1 gene expression; the former loss caused a debilitating skeletal phenotype, whereas the latter conferred a quasi-normal bone mineral phenotype through compensatory homeostatic mechanisms involving Cyp24a1. We found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by inflammatory factors via a process that was unaffected by deletion of the kidney-specific module. These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH) 2 D 3 can fulfill separate functional roles, first in the kidney to control mineral homeostasis and second in extra-renal cells to regulate target genes linked to specific biological responses. Furthermore, we conclude that these mouse models open new avenues for the study of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease.The vitamin D endocrine system serves to regulate mineral homeostasis through its actions in the intestine, kidney, and bone (1). Vitamin D 3 itself is sequentially activated via two specific chemical modifications that occur first in the liver by CYP2R1 to 25(OH)D 3 2 and then in the kidney by CYP27B1 to 1␣,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the active hormonal form of the vitamin (2). Blood levels of 1,25(OH) 2 D 3 are also determined by rates of catabolism that represent the primary function of CYP24A1 in the kidney (3). CYP27B1 is also expressed at low levels in many non-renal target cells (NRTCs), particularly those of skin and the immune system, where local production of 1,25(OH) 2 D 3 has been suggested to preferentially influence the many pleiotropic, non-calcemic functions of 1,25(OH) 2 D 3 (4, 5). Neither the mechanisms nor the overall biological impact of these non-renal cellular sources of 1,25(OH) 2 D 3 are clear, particularly in the context of circulating 1,25(OH) 2 D 3 , which is believed to be derived exclusively from the kidney. Despite these uncertainties, the regulated expression of Cyp27b1 and Cyp24a1 is well-recognized as central to the overall biological activity of the vitamin D endocrine system.Cyp27b1 expressi...

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Section: Endocrine Regulation Of Cyp27b1mentioning

confidence: 99%

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

Meyer

Benkusky

Kaufmann

et al. 2017

Journal of Biological Chemistry

127

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“…Some variants had been described in the literature in association with MS that may act through an effect on circulating VD (Alloza et al, ; Australia New Zealand Multiple Sclerosis Genetics Consortium, ; Cortes et al, ; Karaky et al, ; Laursen et al, ; Manousaki et al, ; Orton et al, ; Ramagopalan et al, ; Ramasamy et al, ; Ross et al, ; Scazzone et al, ; Simon et al, ; Sundqvist et al, ; Zhuang et al, ). No significant intergroup differences were observed for presence of these variants in our cohort.…”

Section: Discussionmentioning

confidence: 99%

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

et al. 2019

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Introduction Vitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case‐control studies that use nonrelated healthy people. Material and Methods We studied 94 individuals from 15 families including at least two patients with MS. We performed whole‐exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types. Results The study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members. Conclusion The study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.

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“…The MS risk allele rs2248359-C increases CYP24A1 expression in the frontal cortex but not in white matter of the human brain ( 92 ). This enzyme was also present in DC and 1,25(OH) 2 D 3 -simulated B cells but without a difference between two alleles in tolerizing/pro-inflammatory DC and B cell ( 52 , 108 ). Taken together, the specific mechanism of how these risk SNPs function in different cell types and contribute to the regulation of gene expression and then the etiology of MS is still unclear as are their possible multiple indirect effects on distant genes or long-term effects amplified by other risk factors during cell activation.…”

Section: The Influence Of Vitamin D and Its Complex Metabolism On Msmentioning

confidence: 93%

“…It has been shown in vitro that this haplotype of CYP27B1 is downregulated in tolerizing DC which could point to a role in an autoimmune pathology ( 52 ). And lower CYP27B1 mRNA expression was associated with rs10877013 (C) in LPS + IFNγ-treated monocytes ( 108 ). Unfortunately, another member of this LD METT21B (previously termed FAM119B ) has been shown to be similarly regulated in the same cell types no matter its gene expression from qPCR or its multiple isoforms from RNA-seq, which prevents a clear conclusion ( 52 ).…”

Section: The Influence Of Vitamin D and Its Complex Metabolism On Msmentioning

confidence: 99%

Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis

Lu¹,

Taylor²,

Körner

2018

Front. Immunol.

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Vitamin D has a plethora of functions that are important for the maintenance of general health and in particular, the functional integrity of the immune system, such as promoting an anti-inflammatory cytokine profile and reducing the Treg/Th17 ratio. Multiple sclerosis (MS) is a chronic, inflammatory, and neurodegenerative central nervous system (CNS) disorder of probable autoimmune origin. MS is characterized by recurring or progressive demyelination and degeneration of the CNS due in part to a misguided immune response to as yet undefined (CNS) antigens, potentially including myelin basic protein and proteolipid protein. MS has also been shown to be associated significantly with environmental factors such as the lack of vitamin D. The role of vitamin D in the pathogenesis and progression of MS is complex. Recent genetic studies have shown that various common MS-associated risk-single-nucleotide polymorphisms (SNPs) are located within or in the vicinity of genes associated with the complex metabolism of vitamin D. The functional aspects of these genetic associations may be explained either by a direct SNP-associated loss- or gain-of-function in a vitamin D-associated gene or due to a change in the regulation of gene expression in certain immune cell types. The development of new genetic tools using next-generation sequencing: e.g., chromatin immunoprecipitation sequencing (ChIP-seq) and the accompanying rapid progress of epigenomics has made it possible to recognize that the association between vitamin D and MS could be based on the extensive and characteristic genomic binding of the vitamin D receptor (VDR). Therefore, it is important to analyze comprehensively the spatiotemporal VDR binding patterns that have been identified using ChIP-seq in multiple immune cell types to reveal an integral profile of genomic VDR interaction. In summary, the aim of this review is to connect genomic effects vitamin D has on immune cells with MS and thus, to contribute to a better understanding of the influence of vitamin D on the etiology and the pathogenesis of this complex autoimmune disease.

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The multiple sclerosis-associated regulatory variant rs10877013 affects expression of CYP27B1 and VDR under inflammatory or vitamin D stimuli

Abstract: The MS-associated variant rs10877013 is a genetic determinant that affects the functioning of the vitamin D system linking environmental and genetic factors.

Cited by 19 publications

References 35 publications

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis

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