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American Journal of Epidemiology, doi:10.1093/aje/kwn142
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Variation in Associations between Allelic Variants of the Vitamin D Receptor Gene and Onset of Type 1 Diabetes Mellitus by Ambient Winter Ultraviolet Radiation Levels: A Meta-Regression Analysis

Anne-Louise Ponsonby1,2, Angela Pezic1, Justine Ellis1,3, Ruth Morley1,4, Fergus Cameron1,4, John Carlin1,4,5 and Terence Dwyer1,2

1 Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia
2 Menzies Research Institute, University of Tasmania, Hobart, Australia
3 Department of Physiology, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
4 Department of Paediatrics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
5 School of Population Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia

Correspondence to Professor Anne-Louise Ponsonby, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia (e-mail: anne-louise.ponsonby{at}mcri.edu.au).

Received for publication December 21, 2007. Accepted for publication May 2, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Vitamin D receptor (VDR) gene polymorphisms may be associated with risk of developing type 1 diabetes mellitus (T1DM), but reports have been conflicting. The authors reexamined population-based case-control studies on selected VDR polymorphisms and T1DM to investigate whether variation in reported associations could be partly explained by differences in ambient winter ultraviolet radiation (UVR) levels. A meta-analysis of 16 studies from 19 regions (midwinter UVR range, 1.0–133.8 mW/m2) was conducted. The association between winter UVR and the log odds ratio was examined by meta-regression. For FokI and BsmI, the log odds ratio for the association between the F and B alleles and T1DM increased as regional winter UVR increased (p = 0.039 and p = 0.036, respectively). The association between the TaqI T allele and T1DM was reduced with increasing winter UVR (p = 0.040). Low winter regional UVR was associated with a higher proportion of controls carrying BsmI and ApaI uppercase alleles and a lower proportion of controls carrying TaqI uppercase alleles. These findings strengthen the case that VDR variants are involved in the etiology of T1DM. They suggest that environmental UVR may influence the association between VDR genotype and T1DM risk. Further work on VDR polymorphisms and T1DM should concomitantly examine the roles of past UVR exposure and vitamin D status.

diabetes mellitus, type 1; genetics; receptors, calcitriol; ultraviolet rays; vitamin D

Abbreviations: CI, confidence interval; UVR, ultraviolet radiation; VDR, vitamin D receptor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The association between vitamin D and the onset of type 1 diabetes mellitus is unclear. To date, environmental and animal studies have provided evidence supporting a possible protective role for higher vitamin D in early life. Vitamin D is largely derived from processes initiated by ultraviolet radiation (UVR) exposure (1). Ambient UVR is inversely associated with latitude (2), and thus diseases linked to vitamin D deficiency such as rickets are more common in high-latitude regions. A latitudinal gradient has also been reported for childhood diabetes (3, 4). In Australia, Staples et al. (5) reported that the latitudinal gradient for type 1 diabetes prevalence in adults reflects a strong negative correlation between ambient UVR and the prevalence of type 1 diabetes. This correlation was higher in magnitude for winter than for summer UVR (5), reflecting the fact that latitudinal gradients in UVR are stronger in winter than in summer.

Although studies on the association between individual-level past UVR exposure and type 1 diabetes have not been conducted, low vitamin D exposure in pregnancy or infancy has been associated with type 1 diabetes in three studies (6, 7), including a cohort study (8). In addition, dietary vitamin D and vitamin D supplementation in pregnancy have been associated with a lower level of type 1 diabetes autoantibodies in early life (9, 10). In a recent meta-analysis, Zipitis and Akobeng (11) reported that type 1 diabetes risk was significantly reduced in infants who received supplemental vitamin D as compared with those who did not (pooled odds ratio = 0.71, 95 percent confidence interval (CI): 0.60, 0.84).

Vitamin D and its analogs exert their actions through the vitamin D receptor (VDR). This nuclear receptor is responsible for transducing the action of the active form of vitamin D, 1,25-hydroxyvitamin D. The gene encoding the vitamin D receptor (VDR) is located in the q13 region of chromosome 12 (12). Polymorphisms within the VDR gene have been associated with altered gene expression or gene function (12). Thus, in view of the reported inverse association between vitamin D and type 1 diabetes, the VDR gene has also been studied. However, in contrast to the interesting associations between environmental markers of vitamin D status and type 1 diabetes risk, the reported associations between variants of the VDR gene and type 1 diabetes have been inconsistent. A recent meta-analysis of four VDR restriction fragment length polymorphisms, FokI, BsmI, ApaI, and TaqI, in relation to type 1 diabetes found no overall association between these VDR gene variants and diabetes risk (13). The FokI variant (dbSNP rs 10735810) is biallelic and can be detected by the presence or absence of a FokI restriction site within the ATG transcriptional start site of the VDR gene. In the presence of the restriction site ("f" allele), the gene is transcribed at normal length. However, in the absence of the restriction site ("F" allele), transcription begins three codons downstream at a second transcription start site. The shorter VDR protein appears to possess elevated transcriptional activity, leading to greater activation of target cells (12, 14, 15). Despite this, the meta-analysis demonstrated a pooled odds ratio for the FokI f allele of only 1.05 (95 percent CI: 0.89, 1.25) (13).

The lack of association between VDR genotype and type 1 diabetes would imply, if VDR genotype were used as an instrumental variable for lifetime vitamin D status, that vitamin D and its associated environmental determinant, UVR, was not part of a causal pathway to type 1 diabetes. However, additional complexities exist. In their meta-analysis, Guo et al. (13) reported heterogeneity for the FokI–type 1 diabetes association. Previously, interaction effects between VDR gene variants and sun exposure (16–19) have been reported for the onset of prostate cancer, another disease in which a past high vitamin D level has been proposed to be a protective factor (20).

Here, we aimed to reexamine the results of population-based case-control studies that have analyzed the association between VDR polymorphisms and type 1 diabetes to see whether the variation between studies could be partly explained by differences in latitude and a latitude-related environmental factor, ambient winter UVR. In addition, we examined whether VDR genotype and winter UVR levels were independent among control populations. We postulated that in low-winter-UVR regions, with little or no vitamin D generated in winter, the prevalence of VDR allelic variants would differ from that in locations where vitamin D generation from UVR could occur year-round.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
We searched the US National Library of Medicine's PubMed database to identify published studies. Keywords used for the search were "vitamin D receptor," "VDR," "type 1 diabetes," "FokI," "BsmI," "ApaI," and "TaqI" and combinations thereof. We included in this assessment the 13 case-control studies (21–33) examined by Guo et al. (13) and three more recently published studies on VDR and type 1 diabetes published through October 2007 (34–36). The usual nomenclature for restriction fragment length polymorphism alleles, following the notation of Guo et al., has been used in this paper. That is, the lowercase allele represents the presence of the restriction site ("f", "b", "a", or "t"), and the uppercase allele represents the absence of the restriction site ("F", "B", "A", or "T").

Regional midwinter UVR readings were then obtained as follows. For each study, we obtained the longitude and latitude of the nearest city. We then used these coordinates to obtain the local long-term average level of midwinter-month (January for the Northern Hemisphere, July for the Southern Hemisphere) noontime erythemal ultraviolet irradiance for the years 1997–2004 from the Total Ozone Mapping Spectrometer database of the US National Aeronautics and Space Administration (37).

Statistical methods
We extended the approach employed by Guo et al. (13) using the meta-regression method to assess whether between-study heterogeneity in the magnitude of the odds ratios representing the association between genotype and type 1 diabetes risk, particularly observed for FokI (13), could be attributed to variation in regional winter UVR. For the FokI gene, there were 12 studies; for BsmI, 16 studies; for ApaI, 11 studies; and for TaqI, 9 studies. In each meta-analysis, the odds ratio was calculated using the presence of the lowercase allele as the reference category (F vs. f, B vs. b, A vs. a, or T vs. t). Log odds ratios were plotted along with 95 percent confidence intervals against the study sites' mean winter UVR levels. We then used meta-regression to examine the association between winter UVR and the log odds ratio (38, 39). Similarly, among controls, the association between the proportion of controls with an uppercase allele and winter UVR classification was examined by meta-regression on the log-odds scale. We also used the meta-regression method to estimate the mean difference in control group allele frequency between sites with average winter UVR levels greater than 28 mW/m2 and less than or equal to 28 mW/m2. Boston, Massachusetts, at 42.2°N, has a midwinter UVR level of 28.6 mW/m2 and is located where winter UVR has been reported to be insufficient to generate previtamin D3 (40). Meta-regression was performed using the "metareg" command (41) in Stata statistical software (Stata, release 10; Stata Corporation, College Station Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 summarizes the characteristics of the 16 studies identified and their results for 19 regions. These studies were located across a range of latitudes from 33°S to 65°N, with a winter UVR range from 1.0 mW/m2 to 133.8 mW/m2. The inverse correlation between latitude and winter UVR level was strong (r = –0.80, p = 0.0002).


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  		TABLE 1. Characteristics of case-control studies included in a meta-regression analysis of vitamin D receptor gene polymorphisms and type 1 diabetes mellitus

 
Meta-regression of odds ratios for the relation between VDR polymorphisms and type 1 diabetes risk by winter UVR level
Figure 1 displays the individual study results for the uppercase allele of each VDR polymorphism by regional winter UVR level, along with the regression lines obtained from the analyses reported in table 2.


Figure 1
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  		FIGURE 1. Odds ratios for the allelic distribution of selected vitamin D receptor polymorphisms and type 1 diabetes mellitus, by ambient midwinter ultraviolet radiation (UVR) levels, and fitted meta-regression line (FokI, p = 0.039; BsmI, p = 0.036; ApaI, p = 0.163; TaqI, p = 0.040; plotted on log scale). The sizes of the circles are proportional to the weight of each study in the meta-regression. Bars, 95% confidence interval.

 

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  		TABLE 2. Meta-regression analysis of the allelic distribution of selected vitamin D receptor gene polymorphisms and type 1 diabetes mellitus, by ambient midwinter ultraviolet radiation level

 
Table 2 summarizes the meta-regression results, providing evidence that for FokI, the magnitude of the odds ratio for the F allele–type 1 diabetes association increased as regional winter UVR level increased (p = 0.039). Similarly, for BsmI, the odds ratio for the F allele–type 1 diabetes association appeared to increase (p = 0.036) as regional winter UVR level increased. For ApaI, there was much less evidence of systematic variation in the association with winter UVR level, while the association between TaqI and type 1 diabetes tended to be reduced with increasing winter UVR level (p = 0.040).

The inclusion of winter UVR level as a covariate in the meta-regression analysis substantially reduced the observed between-study heterogeneity for FokI, BsmI, and TaqI. For example, for FokI, the proportion of variance attributed to heterogeneity in the random-effects model was reduced from 64 percent (95 percent CI: 33, 81) to 44 percent (95 percent CI: 0, 72) by the inclusion of winter UVR.

Meta-regression of the proportion of uppercase alleles among controls
Figure 2 shows that there was marked variation in the proportion of controls with uppercase alleles across studies. We examined whether the proportion of uppercase alleles varied by winter regional UVR level, using the cutoff of ≤28 mW/m2, the midwinter UVR level for Boston, a location where winter UVR is insufficient to generate vitamin D.


Figure 2
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  		FIGURE 2. Proportions of controls carrying the uppercase allele for selected vitamin D receptor polymorphisms, by ambient midwinter ultraviolet radiation (UVR) levels (plotted on log odds scale). The sizes of the circles are proportional to the weight of each study in the meta-regression. Bars, 95% confidence interval.

 
A low winter regional UVR level was associated with higher proportions of BsmI and ApaI uppercase alleles and a lower proportion of TaqI uppercase alleles (table 3). Although the estimated change in proportion per 10-mW/m2 increase in winter UVR level was relatively small (table 3), there was more than a 100-fold variation in winter UVR levels across studies (table 1). The prevalence of the B (cf. b) allele was 20.5 percent (95 percent CI: 6.2, 34.8) higher in study control populations in the low-winter-UVR (≤28 mW/m2) regions than in regions with a higher winter UVR level, and there was a similar difference in the prevalence of the A (cf. a) allele: 23.9 percent (95 percent CI: 12.4, 35.4). On the other hand, the T (cf. t) allele was less common in the low-winter-UVR locations, by 33.6 percent (95 percent CI: 20.8, 46.4).


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  		TABLE 3. Relative change in the odds of controls' carrying the uppercase allele of the vitamin D receptor gene by ambient midwinter ultraviolet radiation level in a meta-regression analysis

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
This review of case-control studies of the association between the FokI, BsmI, ApaI, and TaqI VDR polymorphisms and type 1 diabetes has shown that these associations appear to vary by the regional winter UVR conditions of the original studies. It was observed that for the FokI and BsmI loci, the log odds ratio for the association (uppercase alleles F and B, respectively) with type 1 diabetes increased with increasing regional winter UVR level. That is, these alleles were more likely to be positively associated with type 1 diabetes in high-winter-UVR conditions. The magnitude of the association between the uppercase allele of TaqI and type 1 diabetes was also dependent on winter UVR level, but the association pointed in the opposite direction. These findings suggest that environmental UVR conditions may influence the association between VDR genotype and type 1 diabetes risk.

A strength of this report is that the association between VDR polymorphisms and type 1 diabetes was considered not in isolation but in the context of the environmental conditions that would be likely to influence the significance of functional variations in the VDR gene. These findings are consistent with a growing body of work showing that the association between VDR polymorphisms and disease can vary by either past sun exposure (16–19) or vitamin D level (20, 42–44). Rukin et al. (19) recently commented on the equivocal findings in the literature for VDR polymorphisms and prostate cancer and called for investigators examining the association of VDR genotype with disease to consider sun exposure measures. The findings of this meta-regression analysis support this suggestion.

Here, we allocated studies in the meta-analysis and individuals in the pooled analysis as being exposed to the regional winter UVR of their study location. Thus, exposure misclassification for individual sun exposure could have occurred, because actual personal sun exposure depends on behavior as well as regional ambient UVR. Further, misclassification of life-course regional UVR exposure is possible, since migration history was not considered. However, the effect of such misclassification would have been likely to shift results towards the null and obscure the patterns that we observed. The number of data points in the meta-regression was small, so only linear trends in the magnitude of the log odds ratio were considered, but in reality it is likely that there may be biologic threshold effects for low winter UVR as a proxy for low vitamin D level, above which specific VDR genetic variants are advantageous. Again, our inability to evaluate this fully in the present study may have reduced the likelihood of our finding that the magnitude of the VDR–type 1 diabetes association varies by ambient UVR.

Among the study populations, the proportion of controls with uppercase alleles also appeared to vary according to winter UVR level. In populations located in regions with low winter regional UVR levels (≤28 mW/m2), there appeared to be an overrepresentation of the B and A alleles and an underrepresentation of the T allele. UVR is an important determinant of serum 1,25-hydroxyvitamin D in free-living populations. Thus, it could be hypothesized that evolutionary pressure in different regions has, over time, promoted an increased prevalence of the VDR genotypes that would be beneficial under those conditions. Since the ApaI, TaqI, and BsmI polymorphisms have no known function, they are likely to be acting as markers for one or more functional variants that might affect the potency or expression levels of VDR. Such variants that are in linkage disequilibrium with the B and A alleles might then confer an advantage in regions with low UVR levels. HapMap data (45) (http://www.hapmap.org) show that B and t are in strong linkage disequilibrium in both Caucasian and Asian populations. Therefore, the t allele would also be expected to provide an advantage in this scenario, while T might confer disadvantage consistent with the opposite effect observed in this study.

The observed allelic variation by regional winter UVR level may also relate to ethnicity and skin pigmentation, and in future work researchers should evaluate this. In addition, we have only assessed this issue in studies of type 1 diabetes; many other investigators have also examined VDR in relation to other diseases (46), so a larger pooled study on this issue would be possible.

The Mendelian randomization approach is based on a key assumption that the genotype that is being used as an instrumental variable for an environmental exposure is actually independent of the likelihood of environmental exposure (47, 48). It seems that this assumption is not met here. Thus, it would not appear useful to utilize a Mendelian randomization approach with VDR genotype as an instrumental indicator of life-course vitamin D levels, because the genotype (VDR) and the environment (regional UVR or UVR-related vitamin D levels) are not independent. An important consequence of this is that past null results on the association between the VDR polymorphisms considered here and type 1 diabetes cannot be taken to demonstrate that vitamin D or sun exposure is unimportant in the etiology of type 1 diabetes. In evolutionary terms, it is perhaps not surprising that VDR genotype may vary by environmental UVR conditions and that the association between VDR genotype and type 1 diabetes may depend on environmental UVR context. The findings from this report strengthen the case that VDR variants are involved in the etiology of type 1 diabetes. Further work on the role of VDR polymorphisms in type 1 diabetes should occur in the context of a concomitant examination of the role of past UVR exposure and other environmental determinants of vitamin D status.


   ACKNOWLEDGMENTS
 
The authors thank Kate Ryan for preparation of the ambient UVR data.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. McCollum Award Holick MF. Lecture, 1994: vitamin D—new horizons for the 21st century. Am J Clin Nutr (1994) 60:619–30.[Abstract/Free Full Text]
  2. Roy CR, Gies HP, Toomey S. The solar UV radiation environment: measurement techniques and results. J Photochem Photobiol B: Biol (1995) 31:21–7.[CrossRef]
  3. Diabetes Epidemiology Research International Group. Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes (1988) 37:1113–19.[Abstract]
  4. EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet (2000) 355:873–6.[CrossRef][Web of Science][Medline]
  5. Staples JA, Ponsonby AL, Lim LL, et al. Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environ Health Perspect (2003) 111:518–23.[Web of Science][Medline]
  6. The EURODIAB Substudy 2 Study Group. Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. Diabetologia (1999) 42:51–4.[CrossRef][Web of Science][Medline]
  7. Stene LC, Joner G. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr (2003) 78:1128–34.[Abstract/Free Full Text]
  8. Hypponen E, Laara E, Reunanen A, et al. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet (2001) 358:1500–3.[CrossRef][Web of Science][Medline]
  9. Fronczak CM, Baron AE, Chase HP, et al. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care (2003) 26:3237–42.[Abstract/Free Full Text]
  10. Brekke HK, Ludvigsson J. Vitamin D supplementation and diabetes-related autoimmunity in the ABIS Study. Pediatr Diabetes (2007) 8:11–14.[Web of Science][Medline]
  11. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child (2008) Mar 13 (Epub ahead of print). (doi:10.1136/adc.2007.128579).
  12. Uitterlinden AG, Fang Y, Van Meurs JB, et al. Genetics and biology of vitamin D receptor polymorphisms. Gene (2004) 338:143–56.[CrossRef][Web of Science][Medline]
  13. Guo SW, Magnuson VL, Schiller JJ, et al. Meta-analysis of vitamin D receptor polymorphisms and type 1 diabetes: a HuGE review of genetic association studies. Am J Epidemiol (2006) 164:711–24.[Abstract/Free Full Text]
  14. Jurutka PW, Remus LS, Whitfield GK, et al. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol (2000) 14:401–20.[Abstract/Free Full Text]
  15. Whitfield GK, Remus LS, Jurutka PW, et al. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol (2001) 177:145–59.[CrossRef][Web of Science][Medline]
  16. Bodiwala D, Luscombe CJ, French ME, et al. Polymorphisms in the vitamin D receptor gene, ultraviolet radiation, and susceptibility to prostate cancer. Environ Mol Mutagen (2004) 43:121–7.[CrossRef][Web of Science][Medline]
  17. John EM, Schwartz GG, Koo J, et al. Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer. Cancer Res (2005) 65:5470–9.[Abstract/Free Full Text]
  18. Moon S, Holley S, Bodiwala D, et al. Associations between G/A1229, A/G3944, T/C30875, C/T48200 and C/T65013 genotypes and haplotypes in the vitamin D receptor gene, ultraviolet radiation and susceptibility to prostate cancer. Ann Hum Genet (2006) 70:226–36.[CrossRef][Web of Science][Medline]
  19. Rukin NJ, Luscombe C, Moon S, et al. Prostate cancer susceptibility is mediated by interactions between exposure to ultraviolet radiation and polymorphisms in the 5' haplotype block of the vitamin D receptor gene. Cancer Lett (2007) 247:328–35.[CrossRef][Web of Science][Medline]
  20. Ma J, Stampfer MJ, Gann PH, et al. Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. Cancer Epidemiol Biomarkers Prev (1998) 7:385–90.[Abstract/Free Full Text]
  21. Hauache OM, Lazaretti-Castro M, Andreoni S, et al. Vitamin D receptor gene polymorphism: correlation with bone mineral density in a Brazilian population with insulin-dependent diabetes mellitus. Osteoporos Int (1998) 8:204–10.[CrossRef][Web of Science][Medline]
  22. Chang TJ, Lei HH, Yeh JI, et al. Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population. Clin Endocrinol (Oxf) (2000) 52:575–80.[CrossRef][Medline]
  23. Ban Y, Taniyama M, Yanagawa T, et al. Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population. BMC Med Genet (2001) 2:7. (Electronic article).[CrossRef][Medline]
  24. Gyorffy B, Vasarhelyi B, Krikovszky D, et al. Gender-specific association of vitamin D receptor polymorphism combinations with type 1 diabetes mellitus. Eur J Endocrinol (2002) 147:803–8.[Abstract]
  25. Fassbender WJ, Goertz B, Weismuller K, et al. VDR gene polymorphisms are overrepresented in German patients with type 1 diabetes compared to healthy controls without effect on biochemical parameters of bone metabolism. Horm Metab Res (2002) 34:330–7.[CrossRef][Web of Science][Medline]
  26. Yokota I, Satomura S, Kitamura S, et al. Association between vitamin D receptor genotype and age of onset in juvenile Japanese patients with type 1 diabetes. (Letter). Diabetes Care (2002) 25:1244.[Free Full Text]
  27. Turpeinen H, Hermann R, Vaara S, et al. Vitamin D receptor polymorphisms: no association with type 1 diabetes in the Finnish population. Eur J Endocrinol (2003) 149:591–6.[Abstract]
  28. Motohashi Y, Yamada S, Yanagawa T, et al. Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes. J Clin Endocrinol Metab (2003) 88:3137–40.[Abstract/Free Full Text]
  29. Skrabic V, Zemunik T, Situm M, et al. Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population. Diabetes Res Clin Pract (2003) 59:31–5.[CrossRef][Web of Science][Medline]
  30. Audi L, Marti G, Esteban C, et al. VDR gene polymorphism at exon 2 start codon (FokI) may have influenced type 1 diabetes mellitus susceptibility in two Spanish populations. Diabet Med (2004) 21:393–4.[CrossRef][Web of Science][Medline]
  31. Bianco MG, Minicucci L, Calevo MG, et al. Vitamin D receptor polymorphisms: are they really associated with type 1 diabetes? Eur J Endocrinol (2004) 151:641–2.[CrossRef][Web of Science][Medline]
  32. Zemunik T, Skrabic V, Boraska V, et al. FokI polymorphism, vitamin D receptor, and interleukin-1 receptor haplotypes are associated with type 1 diabetes in the Dalmatian population. J Mol Diagn (2005) 7:600–4.[Abstract/Free Full Text]
  33. San-Pedro JI, Bilbao JR, Perez de Nanclares G, et al. Heterogeneity of vitamin D receptor gene association with celiac disease and type 1 diabetes mellitus. Autoimmunity (2005) 38:439–44.[CrossRef][Web of Science][Medline]
  34. Capoluongo E, Pitocco D, Concolino P, et al. Slight association between type 1 diabetes and "ff" VDR FokI genotype in patients from the Italian Lazio region. Lack of association with diabetes complications. Clin Biochem (2006) 39:888–92.[CrossRef][Web of Science][Medline]
  35. Xiao XH, Liu ZL, Wang H, et al. Effects of vitamin D receptor gene polymorphisms on susceptibility to type 1 diabetes mellitus. Chin Med Sci J (2006) 21:95–8.[Medline]
  36. Garcia D, Angel B, Carrasco E, et al. VDR polymorphisms influence the immune response in type 1 diabetic children from Santiago, Chile. Diabetes Res Clin Pract (2007) 77:134–40.[CrossRef][Web of Science][Medline]
  37. National Aeronautics and Space Administration. Total Ozone Mapping Spectrometer. In: Ozone Processing Team—NASA/GFCS Code 613.3. Data product: erythemal UV exposure (2007) Washington, DC: National Aeronautics and Space Administration. (http://toms.gsfc.nasa.gov/ery_uv/euv.html).
  38. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med (2002) 21:1559–73.[CrossRef][Web of Science][Medline]
  39. Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Stat Med (2003) 22:2693–710.[CrossRef][Web of Science][Medline]
  40. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab (1988) 67:373–8.[Abstract/Free Full Text]
  41. Harbord R, Steichen T. METAREG: Stata module to perform meta-analysis regression. (Statistical software components S446201). (2004) Boston, MA: Department of Economics, Boston College. (Revised February 2, 2005).
  42. Slattery ML, Neuhausen SL, Hoffman M, et al. Dietary calcium, vitamin D, VDR genotypes and colorectal cancer. Int J Cancer (2004) 111:750–6.[CrossRef][Web of Science][Medline]
  43. Slattery ML, Sweeney C, Murtaugh M, et al. Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer. Int J Cancer (2006) 118:3140–6.[CrossRef][Web of Science][Medline]
  44. Han J, Colditz GA, Hunter DJ. Polymorphisms in the MTHFR and VDR genes and skin cancer risk. Carcinogenesis (2007) 28:390–7.[Abstract/Free Full Text]
  45. The International HapMap Consortium. A haplotype map of the human genome. Nature (2005) 437:1299–320.[CrossRef][Medline]
  46. Uitterlinden AG, Fang Y, van Meurs JB, et al. Vitamin D receptor gene polymorphisms in relation to vitamin D related disease states. J Steroid Biochem Mol Biol (2004) 89-90:187–93.
  47. Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol (2004) 33:30–42.[Free Full Text]
  48. Thomas DC, Conti DV. Commentary: the concept of ‘Mendelian randomization.’ Int J Epidemiol (2004) 33:21–5.[Free Full Text]

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C. Wasserfall and M. A. Atkinson
Taking a Daily Vitamin to Prevent Type 1 Diabetes?
Diabetes, January 1, 2009; 58(1): 24 - 25.
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