Elsevier

Cellular Immunology

Volume 279, Issue 1, September 2012, Pages 42-45
Cellular Immunology

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

https://doi.org/10.1016/j.cellimm.2012.08.006Get rights and content

Abstract

CYP2R1 (25α-hydroxylase) catalyzes vitamin D3 to 25-hydroxyvitamin D3, while the CYP27B1 (1α-hydroxylase) catalyzes the 25(OH)D3 to 1, 25(OH)2D3. 1, 25(OH)2D3 prevents the development of autoimmune diabetes. We aimed to investigate CYP2R1 and CYP27B1 genes polymorphisms and susceptibility to type 1 diabetes in children. One hundred and twenty type 1 diabetic patients and One hundred and twenty controls were genotyped for CYP2R1 (rs10741657) and CYP27B1 (rs10877012) polymorphism. GG genotype of CYP2R1 increased risk to develop type 1 diabetes, and CC genotype of CYP27B1 increased risk to develop type 1 diabetes. Our finding suggested that GG genotype of CYP2R1 polymorphism and/or CC genotype of CYP27B1 polymorphism increased the risk of developing of type 1 diabetes in Egyptian children. In addition there was a synergism between GG genotype of CYP2R1 and CC genotype of CYP27B1 regarding the risk of development of type 1 diabetes.

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

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