Inherited Variation in Vitamin D Genes Is Associated With Predisposition to Autoimmune Disease Type 1 Diabetes

Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Diabetes (Impact Factor: 8.1). 03/2011; 60(5):1624-31. DOI: 10.2337/db10-1656
Source: PubMed

ABSTRACT Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.
We measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.
Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10(-4)), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10(-3)) and CYP2R1 (P = 3.0 × 10(-3)).
Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.

Download full-text


Available from: Jason D Cooper, Jun 19, 2014
33 Reads
  • Source
    • "In these GWas meta-analyses, the strongest signals of association were observed in GC (vitamin D binding protein), DHCR7 (7-dehydrocholesterol reductase) and NADSYN1 region, and CYP2R1 (cytochrome P450, family 2, subfamily r, polypeptide 1). smaller scale replication and candidate gene studies in european and asian populations also demonstrated the association of variants in these gene regions with serum 25(OH)D levels (Bu et al. 2010; Cooper et al. 2011; engelman et al. 2013; lu et al. 2012; Zhang et al. 2012). On the other hand, in aas, studies have shown that genetic ancestry contributes to serum 25(OH)D variation (signorello et al. 2010; Yao et al. 2012), but the association of the GWas-identified snPs with serum 25(OH)D levels has not been fully explored. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D deficiency is more common among African Americans (AAs) than among European Americans (EAs), and epidemiologic evidence links vitamin D status to many health outcomes. Two genome-wide association studies (GWAS) in European populations identified vitamin D pathway gene single-nucleotide polymorphisms (SNPs) associated with serum vitamin D [25(OH)D] levels, but a few of these SNPs have been replicated in AAs. Here, we investigated the associations of 39 SNPs in vitamin D pathway genes, including 19 GWAS-identified SNPs, with serum 25(OH)D concentrations in 652 AAs and 405 EAs. Linear and logistic regression analyses were performed adjusting for relevant environmental and biological factors. The pattern of SNP associations was distinct between AAs and EAs. In AAs, six GWAS-identified SNPs in GC, CYP2R1, and DHCR7/NADSYN1 were replicated, while nine GWAS SNPs in GC and CYP2R1 were replicated in EAs. A CYP2R1 SNP, rs12794714, exhibited the strongest signal of association in AAs. In EAs, however, a different CYP2R1 SNP, rs1993116, was the most strongly associated. Our models, which take into account genetic and environmental variables, accounted for 20 and 28 % of the variance in serum vitamin D levels in AAs and EAs, respectively. Electronic supplementary material The online version of this article (doi:10.1007/s00439-014-1472-y) contains supplementary material, which is available to authorized users.
    Human Genetics 08/2014; 133(11). DOI:10.1007/s00439-014-1472-y · 4.82 Impact Factor
  • Source
    • "1,25(OH)2D3 is additionally strongly affected by the serum levels of calcium, phosphate and parathyroid hormone with clinical guidelines still recommending the routine assessment of 25(OH)D3 as the appropriate parameter in order to monitor the VitD status of patients [19]. In this context genetic polymorphisms within key enzymes regulating the pathophysiology of VitD have been shown to affect substantially VitD signaling in clinical diseases [20], [21]. In chronic HCV infection genetic polymorphisms within VitD binding proteins [12], the CYP27B1-hydroxylase [22] and the VitD-receptor [23] have been shown to correlate significantly with the outcome of antiviral therapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24-72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002-1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975-0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000-1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073-2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271-4.695, P = 0.007) constituted the strongest predictors of treatment response. While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
    PLoS ONE 02/2014; 9(2):e87974. DOI:10.1371/journal.pone.0087974 · 3.23 Impact Factor
  • Source
    • "This process leads to removal of that substrate from the synthetic pathway of vitamin D3, a precursor of 25(OH)D. Cooper et al. showed that the rs12785878 T allele was significantly associated with lower levels of 25(OH)D in type 1 diabetic patients [15]. In our study, we found that two variant genotypes of DHCR7/NADSYN1 (rs3829251 and rs12785878) were associated with serum 25(OH)D levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D deficiency rickets is common in China. Genetic factors may play an important role in the susceptibility to rickets. Our study aimed to identify the relationship between three vitamin D-related genes (group specific component [GC], cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and rickets in Han Chinese children from northeastern China. A total of 506 Han children from northeastern China were enrolled in the current study. Twelve SNPs in three candidate genes were genotyped using the SNaPshot assay. Linear regression was used to examine the effect of 12 single-nucleotide polymorphisms (SNPs) on the risk of rickets. In our case--control cohort, six alleles of the 12 SNPs conferred a significantly increased risk of rickets in GC (rs4588 C, P = 0.003, OR: 0.583, 95% CI: 0.412-0.836; rs222020 C, P = 0.009, OR: 1.526, 95% CI:1.117-2.0985; rs2282679 A, P = 0.010, OR: 0.636, 95% CI :0.449-0.900; and rs2298849 C, P = 0.001, OR: 1.709, 95% CI:1.250-2.338) and in CYP2R1 (rs10741657 G, P = 0.019, OR: 1.467, 95% CI:1.070-2.011; and rs2060793 G, P = 0.023, OR: 0.689, 95% CI:0.502-0.944). The results remained significant after adjustment for sex and body mass index. We further analyzed the effect of genotypes under three different genetic models. After using Bonferroni's method for multiple corrections, rs4588, rs2282679, and rs2298849 of the GC gene were significantly associated with rickets under the dominant (P =0.003 for rs4588, P =0.024 for rs2282679, and P =0.005 for rs2298849) and additive models (P = 0.006 for rs4588, P = 0.024 for rs2282679, and P = 0.005 for rs2298849). Haplotype analysis showed that the CAT haplotype of the GC gene (P = 0.005) and the GAA haplotype of the CYP2R1 gene (P = 0.026) were associated with susceptibility to rickets. This case--control study confirmed the strong effect of GC and CYP2R1 loci on rickets in Han children from northeastern China.
    BMC Medical Genetics 09/2013; 14(1):101. DOI:10.1186/1471-2350-14-101 · 2.08 Impact Factor
Show more