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Published online July 2, 2007
Diabetes 56:2616-2621, 2007
DOI: 10.2337/db07-0652
© 2007 by the American Diabetes Association
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Association of the Vitamin D Metabolism Gene CYP27B1 With Type 1 Diabetes

Rebecca Bailey1, Jason D. Cooper1, Lauren Zeitels1, Deborah J. Smyth1, Jennie H.M. Yang1, Neil M. Walker1, Elina Hyppönen2, David B. Dunger3, Elizabeth Ramos-Lopez4, Klaus Badenhoop4, Sergey Nejentsev1, and John A. Todd1

1 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, U.K
2 Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London, U.K
3 Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K
4 Department of Internal Medicine I, Division of Endocrinology, Diabetes, and Metabolism, University Hospital, Frankfurt, Germany

Address correspondence and reprint requests to Prof. John A. Todd, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, WT/MRC building, Addenbrooke's Hospital, Cambridge, CB2 0XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk

Abbreviations: 1{alpha},25(OH)2D, 1{alpha},25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; EFSD, European Foundation for the Study of Diabetes; IL, interleukin; MAF, minor allele frequency; NCBI, National Center for Biotechnology Information; SNP, single nucleotide polymorphism; VDR, vitamin D receptor


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE—Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1{alpha},25-dihydroxyvitamin D (1{alpha},25(OH)2D) could protect from immune destruction of the pancreatic ß-cells. 1{alpha},25(OH)2D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1{alpha}-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 –1260C>A (rs10877012) and +2838T>C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene.

RESULTS—We found evidence of association with type 1 diabetes for CYP27B1 –1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 –1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 x 10–4) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 x 10–3). The combined P value for an association with type 1 diabetes was 3.8 x 10–6. For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23).

CONCLUSIONS—The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes.

Type 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{alpha},25-dihydroxyvitamin D (1{alpha},25(OH)2D), 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{alpha},25(OH)2D 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 meta-analysis also found no evidence of association (10).

Several 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 encodes 1{alpha}-hydroxylase, the enzyme that converts 25(OH)D into 1{alpha},25(OH)2D. However, these results have not been verified. In the present study, we have investigated the association between type 1 diabetes and sequence variants in the CYP27B1 gene. Circulating 1{alpha},25(OH)2D is biologically inactivated through a series of reactions beginning with 24-hydroxylation. Vitamin D 24-hydroxylase is encoded by the CYP24A1 gene located on chromosome 20q13.2-q13.3. Here, we have for the first time also studied the association between type 1 diabetes and CYP24A1 polymorphisms.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We studied a case-control collection comprising 7,854 patients with type 1 diabetes and 8,758 healthy control subjects from the U.K. The recruitment of these subjects and sample processing have been described elsewhere (15). We also studied CYP27B1 polymorphisms in a family collection including 2,774 type 1 diabetes families with one or two affected offspring (815 from the U.K. and Northern Ireland, 841 from Finland, 335 from the U.S., 360 from Norway, and 423 from Romania), providing 3,081 parent-child trio genotypes for CYP27B1 –1260 and 2,198 trio genotypes for CYP27B1 +2838. The collection of all DNA samples has been approved by relevant ethical committees. We obtained written informed consent from all participants.

Genotyping.
In the CYP27B1 gene, we genotyped three single nucleotide polymorphisms (SNPs), CYP27B1 –1260C>A (rs10877012, located in the 5' region) and CYP27B1 +2838T>C (rs4646536, located in intron 6), which were previously reported (11–14), and rs8176345, a synonymous SNP in exon 5 that we found by sequencing. We used HapMap data (16) to select tag SNPs that capture common variants in the CYP24A1 gene. Of the 111 HapMap SNPs located in the region (National Center for Biotechnology Information [NCBI] build 34, coordinates chromosome 20: 53,450,894.0.53,482,103), 54 SNPs had minor allele frequency (MAF) >0.05, and 16 were chosen as tag SNPs that capture association of other common variants with r2 > 0.8. CYP24A1 SNPs were genotyped in up to 5,239 case and 5,539 control subjects (exact numbers for each SNP are shown in Table 3). Genotyping was done using TaqMan (Assay-by-design; Applied Biosystems, Warrington, U.K.; see the online appendix [available at http://dx.doi.org/10.2337/db07–0652]). All genotypes were scored by two researchers independently to minimize error. Genotypes of control subjects and parents did not deviate from Hardy-Weinberg equilibrium above that expected at random (P > 0.05).


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  		TABLE 3 Analysis of 16 tag polymorphisms of the CYP24A1 gene in type 1 diabetic case and control subjects

 
DNA sequencing.
Direct sequencing of nested PCR products from 32 healthy control subjects from the U.K. was performed using an Applied Biosystems 3700 capillary sequencer (Foster City, CA). Polymorphisms were identified using the Staden Package (http://www.mrc-lmb.cam.ac.uk/pubseq/) and mapped to the NCBI human genome build 35.

Statistical analyses.
All statistical analyses were performed within Stata statistical package (http://www.stata.com), using additional Stata routines (http://www-gene.cimr.cam.ac.uk/clayton/software/). We analyzed case and control subjects using logistic regression models (17), adjusting for 12 broad geographical regions, to allow for geographic variation in allele frequencies across the U.K. (18). The families were analyzed using the transmission disequilibrium test (19) and conditional logistic regression (17). A score test was used to combine tests from family and case-control studies as described previously (15). We used htstep, htsearch, and haptag programs within Stata 8.2 to select tag SNPs in the CYP24A1 gene. For these SNPs, we performed a multilocus test using mlpop program in Stata 8.2, which tests for association between disease and the tag SNPs due to linkage disequilibrium with one or more causal variants in the region. It contrasts allele frequencies of a nonredundant set of tag SNPs between case and control subjects by use of Hotelling's t2 test (20,21). We did not apply correction for multiple testing.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Association analysis of the CYP27B1 polymorphisms.
We found evidence that the promoter polymorphism CYP27B1 –1260 is associated with type 1 diabetes in both the case-control (P = 9.6 x 10–4; C/C genotype, odds ratio [OR] 1.22 [95% CI 1.10–1.36]; Table 1) and the family (P = 3.9 x 10–3; C/C genotype, relative risk [RR] 1.33 [95% CI 1.12–1.58]; Table 1) collections. Consequently, when we combined evidence from both collections, which are fully independent from each other, the combined test provided statistical support for an association between type 1 diabetes and CYP27B1 –1260 (P = 3.8 x 10–6 for the 2 degree of freedom [df] genotype model, see Table 1 legend). There was evidence of population heterogeneity in the parent allele frequencies of CYP27B1 –1260 (F3, 3486 = 3.44, P = 0.016) but no evidence for heterogeneity in the disease RR between populations above that expected at random ({chi}62 = 3.11, P = 0.79). We found no evidence of regional heterogeneity in the control allele frequencies (F11, 7261 = 0.86, P = 0.58).


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  		TABLE 1 CYP27B1 –1260 allele and genotype frequencies and association test results in 7,854 case, 8,758 control, and 3,081 parent-child trio genotypes

 
In contrast to other previously published studies (11–14), we found that intronic SNP CYP27B1 +2838 was also associated with type 1 diabetes in both collections. The major allele T was associated with increased type 1 diabetes risk in both the case-control (P = 0.010; T/T genotype, OR 1.20 [95% CI 1.07–1.36]; Table 2) and the family (P = 6.1 x 10–4; T/T genotype, RR 1.36 [1.11–1.67]; Table 2) collections. The combined P value was 8.5 x 10–5 (2-df genotype model, see Table 2 legend).


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  		TABLE 2 CYP27B1 +2838 allele and genotype frequencies and association test results in 5,552 case, 7,435 control, and 2,198 parent-child trio genotypes

 
We noted that in all population samples that we studied, including control subjects from U.K. and parents of the patients from U.K. and Northern Ireland, Norway, or Romania, there is almost perfect linkage disequilibrium between SNPs CYP27B1 –1260 and +2838 with D' = 1.0 and r2 = 0.99 (we obtained lower P values for CYP27B1 –1260 because more samples were genotyped for this SNP than for +2838). To verify genotyping of CYP27B1 –1260 and +2838, we directly sequenced 376 case subjects and 533 control subjects and found complete concordance in the results. This raised the possibility that in the German and Polish population samples studied previously (11–14), there may have been genotyping error in the analysis of CYP27B1 –1260 polymorphism. Therefore, in Cambridge, we re-genotyped 120 DNA samples from 36 type 1 diabetes families from the original German laboratory for the two SNPs, obtaining only 88.2% concordance between the two genotype datasets for CYP27B1 –1260, and this problem was compounded by evidence of data handling errors. Contrary to previous analyses (11,12,14), in these German samples, we found the most perfect linkage disequilibrium between the two SNPs (CYP27B1 –1260 and +2838 SNPs: D' = 1.00 and r2 = 0.99) as we report here for all other populations studied, indicative of past genotyping and data analysis errors.

Resequencing of the CYP27B1 gene.
We then resequenced 8 kb of the CYP27B1 gene, including all exons, introns, and 2 kb 5' and 3' of the gene, using DNA samples of 32 healthy subjects from U.K. to test for the presence of an obvious candidate for a causal variant, such as an amino acid–changing polymorphism or a splice mutation. We discovered two novel rare SNPs with MAFs <0.01, one in the promoter at position –1138 and one in the 3'-untranslated region (ss67078180 and ss67078183, respectively; http://www.ncbi.nlm.nih.gov/SNP/). We did not genotype these SNPs because even large samples that we studied here were underpowered to demonstrate association of such rare variants. We also found a synonymous SNP rs8176345 in exon 5 with MAF = 0.03 that was not in linkage disequilibrium with the common CYP27B1 SNPs at positions –1260 and +2838 (r2 = 0.06 and 0.06, respectively). We genotyped rs8176345 in a subset of the case-control collection comprising 3,040 type 1 diabetic patients and 3,349 control subjects but obtained no evidence of an association (P = 0.23; OR 0.87 [95% CI 0.71–1.09]). We also identified a common promoter SNP rs3782130 at position –1074 with MAF = 0.33. Because we were unable to develop a working high throughput genotyping assay for this SNP, we sequenced it in 376 case subjects and 533 control subjects and found that it was also in almost perfect linkage disequilibrium with SNPs at positions –1260 and +2838 (r2 = 0.99 and 0.97, respectively).

Interaction analyses.
We performed case-only gene-gene interaction tests (15) between known type 1 diabetes susceptibility loci and CYP27B1 –1260. We did not undertake the same analyses for CYP27B1 –2838 because these SNPs are in almost perfect linkage disequilibrium. There was no consistent evidence of an interaction (that is the deviation from a multiplicative model) for the joint effects of CYP27B1 –1260 and INS rs689 (–23HphI), PTPN22 rs2476601 (Arg620Trp), or CTLA4 rs3087243 (Supplementary Table 1). However, there was some evidence for an interaction with HLA-DRB1 (Supplementary Table 1), but when we analyzed CYP27B1 –1260 stratified by specific HLA-DRB1 genotypes, we found that risk ratios were not consistent between the case-control and family collections (Supplementary Table 2). Therefore, we conclude that in conferring risk of type 1 diabetes CYP27B1 does not interact with the previously known disease genes. We conducted a similar interaction analysis for CYP27B1 –1260 and seven VDR SNPs (FokI, ApaI, BsmI, TaqI, rs2544043, rs12721366, and rs4303288) (9,10). However, we found no evidence of an interaction (Supplementary Table 1). We also tested CYP27B1 –1260 for age-at-diagnosis and sex effects in a case-only analysis but did not find evidence for these (Supplementary Table 1) or for parent-of-origin effect in the affected families (P = 0.76).

Analysis of the CYP24A1 gene.
In the case-control collection, we tested 16 tag SNPs that capture association of the common variants that were present in the CYP24A1 gene in HapMap (Table 3). A multilocus test revealed no evidence of association between CYP24A1 polymorphisms and type 1 diabetes (P = 0.23). Therefore, we did not undertake follow-up genotyping of any of the CYP24A1 polymorphisms in additional case and control subjects or families.


   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study provides the first evidence of association between CYP27B1 polymorphisms and type 1 diabetes in a fully validated analysis. Our results in the present report indicate what appears to have been technical and analytical errors in the previous studies (11–14). Nevertheless, these initial reports did contribute to our motivation to carry out the current analysis of CYP27B1 in type 1 diabetes.

Taking into account prior epidemiological and experimental links between vitamin D and type 1 diabetes (3–8,22–27) and the association between CYP27B1 and type 1 diabetes that we established here, we suggest that common inherited variation in the CYP27B1 gene affects vitamin D metabolism and is an etiological factor that predisposes type 1 diabetes. Rare CYP27B1 mutations that completely inactivate 1{alpha}-hydroxylase are known to cause vitamin D–dependent rickets type I (OMIM [Online Mendelian Inheritance in Man] no. 264700), characterized by low concentrations of 1{alpha},25(OH)2D (28,29). We hypothesize that the presence of the CYP27B1 –1260 C allele or another variant in linkage disequilibrium with it (such as two that we have studied here, CYP27B1 +2838 in intron 6 and rs3782130 in the 5' region) reduces the level of the active 1{alpha}-hydroxylase and conversion of 25(OH)Dto 1{alpha},25(OH)2D, leading to increased predisposition to type 1 diabetes. Recently, preliminary data have suggested that type 1 diabetic patients carrying at CYP27B1 –1260 risk genotype CC had lower CYP27B1 mRNA levels in the peripheral blood mononuclear cells compared with healthy control subjects with the CC genotype (30). Functional roles of the CYP27B1 polymorphisms should be investigated in further experiments, evaluating their effects on 1{alpha}-hydroxylase activity and 1{alpha},25(OH)2D concentration, in particular, in the immune cells, such as dendritic cells and monocytes, that underpin immune responses (31,32).

Given our evidence that variation in the CYP27B1 gene etiologically contributes to type 1 diabetes risk, other genes that control vitamin D metabolism are also biologically plausible candidates, and studies of their association with type 1 diabetes are required. Here, we investigated the CYP24A1 gene that encodes vitamin D 24-hydroxylase, an enzyme that inactivates 1{alpha},25(OH)2D, and found no evidence of association. Studies of CYP27A1 or CYP2R1 that encode vitamin D 25-hydroxylases and of the vitamin D–binding protein gene (33,34) are also needed.

In the immune system, 1{alpha},25(OH)2D has been shown to suppress production of the interleukin (IL)-12, IL-2, tumor necrosis factor-{alpha}, and {gamma}-interferon cytokines; to activate expression of transforming growth factor-ß1 and IL-4 cytokines, thereby inhibiting Th1-type responses; and to induce regulatory T-cells (35). It can also regulate differentiation and maturation of dendritic cells critical in induction of T-cell–mediated immune responses (36). These immunomodulatory effects may explain the reported protective effects of vitamin D in type 1 diabetes (37). In the animal models, 1{alpha},25(OH)2D3 and its analogs have been effective in prevention of autoimmune diabetes (23–27) and of other autoimmune diseases (38–42). Epidemiological studies in humans also indicate that intake of vitamin D and its high circulating levels are associated with a lower risk of rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (43–45). Genetic studies reported association of the CYP27B1 polymorphisms with Addison's disease, Hashimoto's thyroiditis, and Graves’ disease (12,13), but these results await confirmation. The possibility that CYP27B1 and 1{alpha},25(OH)2D may be involved in multiple autoimmune diseases suggests that effects of vitamin D on type 1 diabetes involve immune regulation, but this does not rule out additional effects, such as protection of pancreatic ß-cells and their functions.

Our study indicates that genetic variation in the vitamin D metabolism is an etiological factor in type 1 diabetes. This evidence justifies further experiments investigating molecular and cellular actions of vitamin D and mechanisms of its protective effect in type 1 diabetes. Epidemiological studies indicate that vitamin D supplementation in early childhood may reduce type 1 diabetes risk (6–8). Given that vitamin D insufficiency is more common among children and young adults than was previously thought (46), its correction may be a viable approach to prevent type 1 diabetes or delay its development.


   ACKNOWLEDGMENTS
 
This work has received support from the Wellcome Trust and the Juvenile Diabetes Research Foundation International. E.H. is a Department of Health (U.K.) Public Health Career Scientist. E.R.-L. has received support from the European Foundation for the Study of Diabetes (EFSD). K.B. has received support from the EFSD. S.N. is a Diabetes Research and Wellness Foundation Non-Clinical Fellow.

We acknowledge the participation of all of the patients, control subjects, and family members. We thank the Human Biological Data Interchange and Diabetes U.K. for the U.S. and U.K. multiplex families, respectively; the Norwegian Study Group for Childhood Diabetes, D. Undlien, and K. Rønningen for the collection of the Norwegian families; C. Guja and C. Ionescu-Tirgoviste for the collection of the Romanian families; T. Siegmund for the collection of the German families; and B. Widmer for the collection of the British type 1 diabetic patients. We acknowledge use of DNA from the British 1958 Birth Cohort collection (R. Jones, S. Ring, W. McArdle, and M. Pembrey; funded by Medical Research Council Grant G0000934 and Wellcome Trust Grant 068545/Z/02), and we thank D. Strachan and P. Burton for their help. We thank S. Nutland the help in preparing DNA samples and C. Power for the advice on this manuscript.


   FOOTNOTES
 
Published ahead of print at http://diabetes.diabetesjournals.org on 2 July 2007. DOI: 10.2337/db07-0652.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0652.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication May 15, 2007 and accepted in revised form June 27, 2007


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 RESULTS
 DISCUSSION
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