Association of the Vitamin D Metabolism Gene CYP27B1 With Type 1 Diabetes

Abstract

OBJECTIVE-Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1␣,25-dihydroxyvitamin D (1␣,25(OH) 2 D) could protect from immune destruction of the pancreatic ␤-cells. 1␣,25(OH) 2 D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1␣-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes.RESEARCH DESIGN AND METHODS-We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms Ϫ1260CϾA (rs10877012) and ϩ2838TϾC (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene.RESULTS-We found evidence of association with type 1 diabetes for CYP27B1 Ϫ1260 and ϩ2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 Ϫ1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P ϭ 9.6 ϫ 10 Ϫ4 ) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P ϭ 3.9 ϫ 10 Ϫ3 ). The combined P value for an association with type 1 diabetes was 3.8 ϫ 10Ϫ6 . For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P ϭ 0.23). T ype 1 diabetes is strongly inherited and yet exhibits striking epidemiological features such as seasonality in diagnosis, with more cases diagnosed in the autumn and winter months, and a north-south geographical gradient, suggesting inverse correlation between the amount of sunshine and type 1 diabetes incidence (1,2). Lower serum concentrations of 1␣,25-dihydroxyvitamin D (1␣,25(OH) 2 D), the hormonally active form of vitamin D, and of its precursor 25-hydroxyvitamin D (25(OH)D) have been reported at the diagnosis of type 1 diabetes compared with normal control subjects (3-5). Epidemiological studies indicate that vitamin D supplementation in early childhood is associated with decreased type 1 diabetes incidence (6 -8). However, a direct role of impaired vitamin D metabolism in the etiology of type 1 diabetes has not been proven. If vitamin D is a significant factor in type 1 diabetes, then it might be expected that common functional sequence polymorphisms in the genes that influence vitamin D action could predispose to the disease. We have previously studied the gene of the vitamin D receptor (VDR), which binds 1␣,25(OH) 2 D and mediates the effects of vitamin D. We found no association between VDR sequence variants and type 1 diabetes, in contrast to some other studies with smaller sample sizes (9), and a recently conducted metaanalysis also found no evidence of association (10). CONCLUSIONS-TheSeveral studies have reported associations of type 1 diabetes and other autoimmune diseases with polymorphisms in the CYP27B1 gene on chromosome 12q13.1-q13.3 (11-14), which e...

Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring

“…In particular, a cohort study determining the intake of vitamin D and serum concentrations of 25-hydroxyvitamin D 3 would be helpful. The epidemiological surveys performed so far have not taken into account the gene polymorphism for the vitamin D receptor or another gene involved in vitamin D metabolism, which might be linked to type 1 diabetes [29][30][31][32].…”

Single-Nucleotide Polymorphism at CYP27B1-1260, but Not VDR Taq I, Is Possibly Associated with Persistent Hepatitis B Virus Infection

“…CYP27B1-1260 C allele or other variants in the linkage disequilibrium with this allele may reduce the level of the active 1a-hydroxylase and the conversion of 25(OH)D to 1,25(OH) 2 D (Bailey et al, 2007). In view of the preventive and beneficial effect of 1,25(OH) 2 D on both autoimmune diseases and viral infections (Saron et al, 2009;Petta et al, 2010), it seems that the predisposing effect of genetic variation in the CYP27B1 gene may be exerted through the downregulation of 1,25(OH) 2 D levels.…”

“…The CYP27B1-1260 promoter polymorphism has been demonstrated to be related to autoimmune diseases (Lopez et al, 2004;Bailey et al, 2007;Sundqvist et al, 2010), with the CC genotype and C allele being associated with an increased risk of type 1 diabetes (Bailey et al, 2007) and autoimmune Addison's disease (Fichna et al, 2010). This polymorphism is also recently shown to influence the 1,25(OH) 2 D serum levels and treatment response in chronic HCV infection, with the CC genotype being associated with reduced 1,25(OH) 2 D levels and lower sustained virologic response to the treatment with interferon (IFN)-a-based regimens (Lange et al, 2011).…”

“…Single-nucleotide polymorphisms (SNPs) in the VDR gene on chromosome 12q12-q14 have been shown to be associated with distinct clinical phenotypes, except HCC (Huang et al, 2010), and severity of liver disease in HBV infection (Suneetha et al, 2006) with conflicting findings . The CYP27B1-1260 promoter polymorphism has been demonstrated to be associated with autoimmune diseases (Lopez et al, 2004;Bailey et al, 2007;Sundqvist et al, 2010). Moreover, this polymorphism was recently shown to influence the 1,25(OH) 2 D serum levels and treatment response in chronic HCV infection (Lange et al, 2011).…”

Vitamin D and diabetes mellitus: an update 2013

“…Some specific VDR gene haplotypes appear to protect against diabetes, while polymorphisms in the CYP27B1 gene have been shown to affect diabetes susceptibility (56,57). Given the evidence that variation in the CYP27B1 etiologically contributes to T1D risk, other genes that control vitamin D metabolism are also biologically plausible candidates, and should be studied.…”