Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children
Highlights
• CYP2R1 GG genotype increases the risk of type 1 diabetes in Egyptian children. • CYP27B1 CC genotype increases the risk of type 1 diabetes in Egyptian children. • Synergism between GG and CC genotypes regarding the development of type 1 diabetes.
Introduction
Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The incidence of type 1 diabetes varies with geographic patterns. A correlation between higher incidence of type 1 diabetes and lower annual average temperatures or increasing latitudes, has been found [1]. Also, low serum levels of 25(OH)D3 and 1,25(OH)2D3 correlate with an impaired function of the immune system and have been associated with this disease [2].
The synthesis of the most active vitamin D metabolite, 1,25(OH)2D3, requires two hydroxylations, one at the 25 and one at the 1α positions. In the liver, the CYP2R1 (25-hydroxylase) catalyzes vitamin D3 to 25-hydroxyvitamin D3 (25(OH)D3), the main circulating vitamin D metabolite, while the CYP27B1 (1α-hydroxylase) catalyzes the 25(OH)D3 to 1,25(OH)2D3 in the kidney [3].
The CYP2R1 gene is located on the chromosome 11p15.2, contains 5 exons and spans about 15.5 kb [4]. A transition mutation in exon 2 of the CYP2R1 gene is found, which causes the substitution of Pro → Leu at amino acid 99 in the CYP2R1 protein and eliminates vitamin D 25-hydroxylase enzyme activity [5]. The CYP27B1 gene is located on chromosome 12q.13.1–13.3 [6].
1,25(OH)2D3 was shown to inhibit antigen-induced T-cell proliferation and cytokine production. It inhibits IL-12 production, and IL-12 has been shown to exert an important role in the development of type 1 diabetes [7].
This role of the vitamin D system in type 1 diabetes prompted us to investigate the association between CYP2R1 and CYP27B1 genes polymorphism and susceptibility to type 1 diabetes in Egyptian children.
Section snippets
Subjects
The present study comprised 120 patients with type 1 diabetes mellitus. All fulfilled World Health Organization and the American Diabetes Association criteria [8]. Characteristics of the patients are presented in Table 1. They were recruited from endocrinology unit of the Pediatrics Department, Zagazig University Hospitals (Egypt). All patients were subjected to full history taking to identify family history of diabetes mellitus, presentation and age of onset of the disease, insulin regimen and
CYP2R1 and CYP27B1 polymorphism genotypes and alleles distribution and risk of Type 1 diabetes
(Table 2) The genotype frequencies of the CYP2R1 and CYP27B1 were in agreement with Hardy–Weinberg equilibrium in all groups. In type 1 diabetic patients, the frequencies of GG genotype of CYP2R1 were significantly increased compared to control group (29.2% versus 48.3%). Subjects with GG genotype of CYP2R1 were more likely to develop type 1 diabetes (OR = 2.6, 95% CI = 1.1–6.1, P = 0.03). Regarding the CYP27B1 polymorphism, the frequencies of CC genotype were increased in diabetic group compared to
Discussion
In the present study, we analyzed the association of CYP27B1 and CYP2R1 genes polymorphism and type 1 diabetes in Egyptian children and their effect on the 25-hydroxyvitamin D levels.
The novel finding in the present study was the presence of a synergism between GG genotype of CYP2R1 polymorphism and CC genotype of CYP27B1 polymorphism and the risk of development of type 1 diabetes in Egyptian children. To the best of our knowledge, this is the first study to report such an association.
The
Conclusion
Our data suggested that GG genotype of CYP2R1 polymorphism and CC genotype of CYP27B1 polymorphism increase the risk of developing of type 1 diabetes in Egyptian children. In addition there is a synergism between GG genotype of CYP2R1 and CC genotype of CYP27B1 regarding the risk of development of type 1 diabetes. Further genomic investigations in larger groups as well as functional studies should be performed to confirm our findings.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector
References (26)
- et al.
De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25- hydroxylase
J. Biol. Chem.
(2003) - et al.
CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients
J. Steroid Biochem. Mol. Biol.
(2007) - et al.
Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families
Am. J. Hum. Genet.
(1998) - et al.
Expression of 25-hydroxyvitamin D3-1α-hydroxylase in pancreatic islets
J. Steroid Biochem. Mol. Biol.
(2004) - et al.
Identification of a Vitamin D response element in the human insulin receptor gene promoter
J. Steroid Biochem. Mol. Biol.
(2003) Geographic patterns of childhood insulin-dependent diabetes mellitus
Diabetes Metab. Res. Rev.
(1998)- et al.
Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes
Horm. Metab. Res.
(2005) - et al.
Current understanding of the molecular actions of vitamin D
Physiol. Rev.
(1998) - et al.
Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
Proc. Natl. Acad. Sci. USA
(2004) - et al.
CYP27B1 polymorphisms variants are associated with type 1 diabetes mellitus in Germans
J. Steroid Biochem. Mol. Biol.
(2004)
A 1α,25-Dihydroxyvitamin D3 analog enhances regulatory t-cells and arrests autoimmune diabetes in nod mice
Diabetes Metab. Res. Rev.
Diagnosis and classification of diabetes mellitus
Diabetes Care
Vitamin D Insufficiency
N. Engl. J. Med.
Cited by (48)
Vitamin D, inflammation, and cancer
2023, Feldman and Pike's Vitamin D: Volume Two: Disease and TherapeuticsVitamin D and type 1 diabetes
2023, Feldman and Pike's Vitamin D: Volume Two: Disease and TherapeuticsAssociation of vitamin D deficiency with vitamin D binding protein (DBP) and CYP2R1 polymorphisms in Iranian population
2021, Meta GeneCitation Excerpt :Furthermore, CYP2R1 gene (located on 11p15 with 5 exons) contains the main SNP, rs10741657, associate with vitamin D levels as well. The transition mutation on exon 2 brings about the substitution of G/A nucleotides, which subsequently stop vitamin D 25-hydroxylase's enzyme activity (Hussein et al., 2012). Despite the fact that there is a sufficient index of UV-B in the south of Iran due to its geographical location, vitamin D deficiency cases have been reporting regularly which would represent some other reasons associated with vitamin D deficiencies like DBP and CYP2R1 SNPs.
Triangular relationship between CYP2R1 gene polymorphism, serum 25(OH)D<inf>3</inf> levels and T2DM in a Chinese rural population
2018, GeneCitation Excerpt :Pibiri and colleagues suggested that the rs12794714 polymorphism was related to colon cancer in African-Americans (Pibiri et al., 2014). In Egyptian children, an association between the rs10741657 polymorphism and T1DM was observed (Hussein et al., 2012). However, until now, only one study has investigated the relationship between polymorphisms of CYP2R1 gene (rs10741657) and T2DM.
Exploring the link between vitamin D deficiency and obstructive sleep apnea: A comprehensive review
2024, Journal of Sleep ResearchAnalysis of single nucleotide polymorphisms associated with the vitamin D pathway in the placentas of women with gestational diabetes mellitus: a laboratory study
2023, Journal of Yeungnam Medical Science