Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children

hussein, atef; Mohamed, Randa H.; Alghobashy, Ashgan Abdallah

doi:10.1016/j.cellimm.2012.08.006

Cited by 57 publications

(35 citation statements)

References 20 publications

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“…Later studies, one from Egypt with 240 subjects and another one with a large collective (population different countries: British, Finland, USA, Norway, Romania) confirmed these findings [91,93]. Additionally, Bailey et al (2007) showed also an association of T1D with the rs4646536 SNP.…”

Section: Vitamin D Pathwaysmentioning

confidence: 89%

“…Numerous studies focused on VDR SNPs but only few on other genes of the vitamin D pathway [56,57,67,74,88,89,90,91,92,93,94,95,96,97,98,99]. Table 4 presents a summary of association studies for SNPs within the genes CYP2R1 [57,88], CYP27B1 [57,90,91,93], DBP [96,97] as well as cubilin [99] and T1D.…”

Section: Vitamin D Pathwaysmentioning

confidence: 99%

“…Table 4 presents a summary of association studies for SNPs within the genes CYP2R1 [57,88], CYP27B1 [57,90,91,93], DBP [96,97] as well as cubilin [99] and T1D.…”

Section: Vitamin D Pathwaysmentioning

confidence: 99%

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Inherited Variation in Vitamin D Genes and Type 1 Diabetes Predisposition

Penna-Martinez

Badenhoop

2017

Genes

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The etiology and pathophysiology of type 1 diabetes remain largely elusive with no established concepts for a causal therapy. Efforts to clarify genetic susceptibility and screening for environmental factors have identified the vitamin D system as a contributory pathway that is potentially correctable. This review aims at compiling all genetic studies addressing the vitamin D system in type 1 diabetes. Herein, association studies with case control cohorts are presented as well as family investigations with transmission tests, meta-analyses and intervention trials. Additionally, rare examples of inborn errors of vitamin D metabolism manifesting with type 1 diabetes and their immune status are discussed. We find a majority of association studies confirming a predisposing role for vitamin D receptor (VDR) polymorphisms and those of the vitamin D metabolism, particularly the CYP27B1 gene encoding the main enzyme for vitamin D activation. Associations, however, are tenuous in relation to the ethnic background of the studied populations. Intervention trials identify the specific requirements of adequate vitamin D doses to achieve vitamin D sufficiency. Preliminary evidence suggests that doses may need to be individualized in order to achieve target effects due to pharmacogenomic variation.

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Section: Vitamin D Pathwaysmentioning

confidence: 89%

Section: Vitamin D Pathwaysmentioning

confidence: 99%

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Inherited Variation in Vitamin D Genes and Type 1 Diabetes Predisposition

Penna-Martinez

Badenhoop

2017

Genes

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“…Previous studies have shown that the CYP2R1 gene is associated with several vitamin D related diseases including type 1 diabetes41, polycystic ovary syndrome42, and ovarian cancer43. As a microsomal vitamin D 25-hydroxylase in humans, cytochrome P450 2R1 converts vitamin D into 25(OH)D. Given that it is responsible for 25(OH)D productions from a biological precursor, it is very plausible for mutations in this gene to contribute to variations in baseline serum 25(OH)D, and indeed this has been shown to be the case.…”

Section: Discussionmentioning

confidence: 99%

SNP rs11185644 of RXRA gene is identified for dose-response variability to vitamin D3 supplementation: a randomized clinical trial

Zhang

Zhao

Zhou

et al. 2017

Sci Rep

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The level of serum 25-Hydroxyvitamin D [25(OH)D] has high heritability, suggesting that genes may contribute to variations in serum 25(OH)D level and vitamin D dose-response. As vitamin D deficiency has been linked to numerous diseases, understanding how genetic variation contributes to vitamin D dose-response is important for personalized vitamin D treatment and cost-effective disease prevention. To identify genetic variants responsible for vitamin D status and dose-response, we performed two vitamin D3 and calcium clinical supplementation trials in 2,207 postmenopausal Caucasian women. We examined the association of 291 SNPs with baseline serum 25(OH)D levels and 25(OH)D dose-response. Five SNPs, rs10500804 (P = 4.93 × 10−7), rs2060793 (P = 6.63 × 10−7), rs10741657 (P = 1.49 × 10−6), rs10766197 (P = 1.05 × 10−5) and rs11023380 (P = 7.67 × 10−5) in the CYP2R1 gene, as well as 6 SNPs, rs4588 (P = 7.86 × 10−7), rs2298850 (P = 1.94 × 10−6), rs1155563 (P = 6.39 × 10−6), rs705119 (P = 2.80 × 10−5), rs705120 (P = 1.08 × 10−4) and rs222040 (P = 1.59 × 10−4) in the GC gene were associated with baseline serum 25(OH)D levels. SNP rs11185644 near the RXRA was significantly associated with 25(OH)D dose-response (P = 1.01 × 10−4). Our data suggest that polymorphisms in the CYP2R1 and GC gene may contribute to variation in baseline serum 25(OH)D concentration, and that polymorphism rs11185644 may contribute to variation in 25(OH)D dose-response in healthy postmenopausal Caucasian women.

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“…The former is consistent with liver being the major site of 25-hydroxylation, but its abundance in testis awaits further investigation to decipher the physiological relevance, although it has been linked to male reproduction, testicular cancer, and other testiculopathic conditions (33)(34)(35). Cyp2r1 polymorphisms have been implicated in the variation of circulating 25(OH)D 3 concentrations (36)(37)(38) and as risk factors in type 1 diabetes and multiple sclerosis in humans (39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

Zhu

Ochalek

Kaufmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

267

142

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Bioactivation of vitamin D consists of two sequential hydroxylation steps to produce 1α, 25-dihydroxyvitamin D 3 . It is clear that the second or 1α-hydroxylation step is carried out by a single enzyme, 25-hydroxyvitamin D 1α-hydroxylase CYP27B1. However, it is not certain what enzyme or enzymes are responsible for the initial 25-hydroxylation. An excellent case has been made for vitamin D 25-hydroxylase CYP2R1, but this hypothesis has not yet been tested. We have now produced Cyp2r1 −/− mice. These mice had greater than 50% reduction in serum 25-hydroxyvitamin D 3 . Curiously, the 1α,25-dihydroxyvitamin D 3 level in the serum remained unchanged. These mice presented no health issues. A double knockout of Cyp2r1 and Cyp27a1 maintained a similar circulating level of 25-hydroxyvitamin D 3 and 1α,25-dihydroxyvitamin D 3 . Our results support the idea that the CYP2R1 is the major enzyme responsible for 25-hydroxylation of vitamin D, but clearly a second, as-yet unknown, enzyme is another contributor to this important step in vitamin D activation. 25-Hydroxyvitamin D 1a-hydroxylase CYP27B1 (CYP27B1) has long been identified as the sole 25(OH)D 3 1α-hydroxylase in a number of species, including human (5), whereas the specific vitamin D 3 25-hydroxylase has yet to be elucidated. Many candidates have been proposed, but in vivo proof has yet to appear. Most of the potential 25-hydroxylases are primarily expressed in the liver, and all are members of the cytochrome P450 family (CYP2C11, CYP2D25, CYP27A1, CYP3A4, CYP2R1, and CYP2J2/3) (4). Among them, CYP27A1 and CYP2R1 are considered the most promising candidates for vitamin D 25-hydroxylation. CYP27A1, also known as the sterol 27-hydroxylase, is a key enzyme in bile acid formation (6, 7). Recombinant CYP27A1 is able to catalyze multiple oxidation reactions with broad substrate specificity in vitro (8)(9)(10)(11)(12)(13)(14). However, it is a lowaffinity, high-capacity vitamin D 25-hydroxylase and is certainly involved in steroidogenesis. Ablation of Cyp27a1 in mouse disrupted cholesterol metabolism and bile acid synthesis severely but did not alter vitamin D metabolism (15, 16). Indeed, these animals had supranormal serum 25(OH)D 3 levels (15). Patients with cerebrotendinous xanthomatosis caused by mutations in the Cyp27a1 gene show dysfunctions that result from reduced bile acid production, but generally do not present vitamin D-related pathology (17, 18). These findings suggest that CYP27A1 is a minor factor, if it plays a role at all, in 25(OH)D 3 synthesis in vivo. CYP2R1 was recently identified as vitamin D 25-hydroxylase in mouse and human through the screening of a liver cDNA library from Cyp27a1-null mice (19). Heterologous expression of CYP2R1 in HEK cells, yeast, and Escherichia coli revealed that CYP2R1 catalyzes 25-hydroxylation of both vitamin D 3 and vitamin D 2 at similar rate, and much more efficiently than CYP27A1 (19-21). The clinical relevance of CYP2R1 as vitamin D 25-hydroxylase is from a handful of patients of Nigerian and Saudi Arabian decent havi...

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Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children

Cited by 57 publications

References 20 publications

Inherited Variation in Vitamin D Genes and Type 1 Diabetes Predisposition

Inherited Variation in Vitamin D Genes and Type 1 Diabetes Predisposition

SNP rs11185644 of RXRA gene is identified for dose-response variability to vitamin D3 supplementation: a randomized clinical trial

CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo

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