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Am J Clin Nutr 89: 634-640, 2009. First published December 30, 2008; doi:10.3945/ajcn.2008.26445
 American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26445
Vol. 89, No. 2, 634-640, February 2009
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© 2009 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women

Marc Sinotte1,2,3, Caroline Diorio1,2,3, Sylvie Bérubé1,2,3, Michael Pollak1,2,3 and Jacques Brisson1,2,3

1 From the Département de Médecine Sociale et Préventive, Université Laval, Québec, Canada (MS, CD, and JB); the Unité de Recherche en Santé des Populations, Centre Hospitalier Affilié Universitaire de Québec, Québec, Canada (MS, CD, SB, and JB); the Centre des Maladies du sein Deschênes-Fabia, Centre Hospitalier Affilie Universitaire de Québec, Québec, Canada (CD, SB, and JB); and the Cancer Prevention Research Unit, Lady Davis Institute of the Jewish General Hospital and McGill University, Departments of Medicine and Oncology, Montréal, Canada (MP).

2 Supported in part by grant 4811-82 from the Canadian Breast Cancer Research Alliance, a grant from the Translation Acceleration Grants Program for Breast Cancer Control of the Canadian Breast Cancer Research Alliance and the Canadian Institutes of Health Research. MS was supported by studentships from the Canadian Institutes of Health Research and National Cancer Institute of Canada. CD was supported by a postdoctoral fellowships from the Cancer Research Society Inc and the Canadian Institutes of Health Research.

3 Reprints not available. Address correspondence to C Diorio, Unité de Recherche en Santé des Populations, Hôpital du Saint-Sacrement du Centre Hospitalier Affilié Universitaire de Québec, 1050 Chemin Sainte-Foy, Québec, Canada G1S 4L8. E-mail: caroline.diorio{at}uresp.ulaval.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Vitamin D status, determined on the basis of 25-hydroxyvitamin D [25(OH)D] concentrations, is associated with the risk of several diseases. Vitamin D binding protein (DBP) is the major carrier of vitamin D and its metabolites, but the role of DBP single nucleotide polymorphisms (SNPs) on 25(OH)D concentrations is unclear.

Objective: The objective was to evaluate the association of 2 DBP gene SNPs with 25(OH)D concentrations and explore whether such association varies according to the amount of vitamin D that needs to be transported.

Design: This cross-sectional study included 741 premenopausal white women, mostly of French descent. Plasma 25(OH)D concentrations were measured by radioimmunoassay. DBP-1 (rs7041) and DBP-2 (rs4588) were genotyped with a Sequenom MassArray platform. Associations and interactions were modeled by using multivariate linear regression.

Results: DBP-1 and DBP-2 SNPs were in strong linkage disequilibrium and were both associated with 25(OH)D concentrations. An additional copy of the rare allele of DBP-1 or DBP-2 was associated with lower 25(OH)D concentrations (β = –3.29, P for trend = 0.0003; β = –4.22, P for trend < 0.0001, respectively). These DBP polymorphisms explained as much of the variation in circulating 25(OH)D as did total vitamin D intake (r2 = 1.3% for DBP-1, r2 = 2.0% for DBP-2, and r2 ≤ 1.2% for vitamin D intake).

Conclusion: Circulating 25(OH)D concentrations in premenopausal women are strongly related to DBP polymorphisms. Whether DBP rare allele carriers have a different risk of vitamin D–related diseases and whether such carriers can benefit more or less from dietary interventions, vitamin D supplementation, or sun exposure need to be clarified.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Higher vitamin D intakes or circulating concentrations are associated with a lower risk of several chronic illnesses, including common cancers, autoimmune diseases, infectious diseases, and cardiovascular diseases (reviewed in 1, 2). A better understanding of vitamin D biology may prove useful in clarifying these effects and designing effective interventions.

The principal circulating vitamin D metabolite, 25-hydroxyvitamin D [25(OH)D], is recognized (3) as the best short-term biomarker of total exposure to vitamin D (ingested from food or dietary supplements and produced by the skin after sun exposure). More than 99% of 25(OH)D is bound to plasma protein (4), of which {approx}90% is bound to the vitamin D binding protein (DBP) (5). DBP, also known as Gc-globulin, is a member of the albumin (ALB) and alpha-fetoprotein (AFP) gene family. It is mainly synthesized in the liver, where 25(OH)D is also produced. Serum concentrations of DBP range between 4 and 8 µmol/L. DBP has a short half-life of 2.5–3 d compared with 1 to 2 months for 25(OH)D (reviewed in 6–8). The precise role of DBP in vitamin D action is still incompletely understood, but DBP concentrations do not seem to be influenced by vitamin D sterols or other calciotropic hormones or by seasonal variation (reviewed in 7). DBP is significantly elevated during pregnancy and estrogen therapy (9–11) and is low after liver diseases (4, 12), nephrotic syndrome, and malnutrition, probably because of a diminished synthesis rate or excessive protein loss (reviewed in 7).

Until now, little has been known about the influence of DBP polymorphisms on circulating 25(OH)D concentrations, but differences in the coding of amino acids could affect the concentration of the binding protein or its affinity for vitamin D metabolites. In this study we assessed the association of 2 single nucleotide polymorphisms (SNPs) located on exons of the vitamin D binding protein gene (rs7041 and rs4588) with plasma 25(OH)D concentrations and explored whether these associations vary according to the amount of vitamin D that needs to be transported.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population and recruitment procedures
The study design and methods were published previously (13, 14). Briefly, 783 premenopausal women who underwent screening mammography between February and December 2001 were recruited at the Clinique Radiologique Audet (Québec, Canada). Eligible women had no personal history of cancer or breast surgery, had no endocrine diseases, never took selective estrogen-receptor modulators, and had not used hormonal derivatives in the 3 mo before blood sampling. Of the 783 eligible women, 741 provided written informed consent to use their blood samples for assays other than those planned at recruitment (14) and had DNA available (15). This study was approved by the Research Ethics Review Board–Hôpital du Saint-Sacrement du CHA de QuéFormula ec.

Data collection
Anthropometric measurements and blood samples were taken at recruitment. Breast cancer risk factors were documented by telephone interview, including reproductive and menstrual history, family history of breast cancer, personal history of breast biopsies, past use of exogenous hormones, smoking status, alcohol intake, education, and physical activity. Finally, diet was assessed with a self-administered 161-item semiquantitative food-frequency questionnaire (97GP copyrighted at Harvard University, Boston, MA).

Assessment of plasma 25(OH)D
At the time of collection, blood constituents were rapidly stored in aliquots at –80°C until analyzed. Plasma 25(OH)D concentrations were measured between November 2005 and January 2006 by radioimmunoassay after acetonitrile extraction (DiaSorin Inc, Stillwater, MN). The intrabatch and between-batch CVs were 7.3% and 8.8%, respectively (4 blinded duplicates on average for each of the 24 batches), and the results met the performance target set by the international 25-hydroxyvitamin D External Quality Assessment Scheme (DEQAS) Advisory Panel in 2004–2005.

DNA extraction and SNP genotyping
Genotyping procedures were described previously (15). Briefly, DNA was extracted from the buffy coat by using the PUREGene DNA extraction kit (Gentra Inc, Minneapolis, MN) following the manufacturer's protocol, and DNA samples were then blindly genotyped. The rs7041 and rs4588 SNPs, resulting in a T-to-G transversion [an aspartic acid (Asp: GAT) to a glutamic acid (Glu: GAG)] and a C-to-A transversion [a threonine (Thr: ACG) to a lysine (Lys: AAG)], respectively, in exon 11 of DBP (16) were assessed by using the Sequenom MassArray (Sequenom Inc, San Diego, CA) genotyping platform according to the manufacturer's protocol. Each 96-well plate included negative (no DNA) and positive controls to ensure genotyping accuracy. Genotyping call rates were 98.7% for both DBP-1 (rs7041) and DBP-2 (rs4588). The protocol can be provided on request. In this study, concordance of genotyping from the new Sequenom MassArray platform was compared with Fluorescent Polarization–Single Base Extension platform on 10% of the samples; concordance was 100%.

Statistical methods
Crude and adjusted associations of plasma 25(OH)D concentrations with 6 continuous and 3 categorical potential explanatory variables (reviewed in 3, 17) were estimated by using generalized linear models (GLMs). Season of blood collection and leisure-time physical activity [metabolic equivalent (MET)-h/wk] in the past year (proxy variables for sun exposure), total vitamin D (IU/d) and total calcium (mg/d) intakes from food and supplements in the past year, body mass index (BMI; in kg/m2), smoking status, education, and age (y) were included in our analyses. Total energy intake (kcal/d) in the past year was also included in the models.

Deviation from the Hardy-Weinberg equilibrium was assessed for each SNP by a chi-square test with one df, and linkage disequilibrium strength was evaluated with r and Lewontin's D’ statistic between SNPs. Univariate and multivariate-adjusted mean circulating plasma 25(OH)D concentrations by category of genotypes under codominant mode of inheritance were estimated by using GLM models. Trends between the number of copies of the rare allele, entered as a continuous variable (0, 1, or 2), and concentrations of 25(OH)D were evaluated by linear regression models where the β coefficients represent the per allele variation in nmol/L of plasma 25(OH)D concentration. The strength of associations of genotypes to 25(OH)D concentrations among women with a high vitamin D load was compared with that among women with a low vitamin D load by using the above models to which an interaction term was added. The P value of these interaction terms between vitamin D loads (low or high) and the genotypes under the codominant mode of inheritance were used to assess the effect modification of vitamin D load. Periods of low and high vitamin D loads were chosen based on the seasonal variation in 25(OH)D seen in this cohort (13). Data collected throughout year 2001 were dichotomized in two 6-mo periods during which the vitamin D load is expected to be high (May to October; median 25(OH)D concentration = 68.6 nmol/L) or low (November to April; median 25(OH)D = 54.1 nmol/L).

Partial r2 values, generated from the adjusted GLM models as the ratio of type II sum of squares on the total sum of squares, were mutually adjusted and interpreted as the independent contribution of each variable in the model to the explanation of the variation in 25(OH)D concentrations.

Assumption of normality of residuals from these analyses was met with untransformed variables. Neither multicollinearity nor influential observation was detected. All tests were 2-sided and carried out by using SAS version 9.1 (SAS Institute Inc, Cary, NC), and a nominal P value of 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Determinants of 25(OH)D concentrations
Characteristics of the study population are described in detail elsewhere (14). Briefly, 741 premenopausal women in the present study had a mean (±SD) age of 46.8 ± 4.6 and plasma 25(OH)D concentration of 64.9 ± 19.6. The mean (±SD) leisure-time physical activity and BMI were 27.1 ± 22.2 MET-hour/wk and 25.2 ± 4.6, respectively. The mean (±SD) total daily vitamin D, total daily calcium, and total daily energy intakes were of 284 ± 232 IU, 969 ± 433 mg, and 1907 ± 515 kcal, respectively. The percentage of university and college compared with secondary school degree or less and of nonsmokers compared with smokers and former smokers were 61.9% and 44.9%, respectively.

Several variables were associated with 25(OH)D concentrations (Table 1). Mean plasma 25(OH)D was much higher among women recruited in summer than in those recruited in winter (difference = 21.7 nmol/L; an increase of 38%). Leisure-time physical activity was positively related to 25(OH)D concentrations (P < 0.001), as were total vitamin D (P = 0.0014) and total calcium (P < 0.001) intakes. BMI was negatively associated with 25(OH)D concentrations (P < 0.001), as were total energy intake and education (both P < 0.05). Smokers tended to have higher 25(OH)D concentrations than nonsmokers, although this difference was statistically significant only for ex-smokers. Concentrations of 25(OH)D tended to decrease as age increased in this population of premenopausal women, although this association was not statistically significant (P = 0.12).


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  		TABLE 1. Relation between plasma 25-hydroxyvitamin D [25(OH)D] concentrations and potentially explanatory variables in premenopausal women

 
Vitamin D binding protein SNPs and 25(OH)D concentrations
No significant deviation from Hardy-Weinberg expectations was observed for polymorphisms DBP-1 (P = 0.19) and DBP-2 (P = 0.48). Linkage disequilibrium between these SNPs was almost complete (D’ = 1.00, r = 0.74). In crude or adjusted models, rare allele carriers had lower circulating 25(OH)D concentrations than did homozygotes for the common allele (Table 2). Each additional rare allele was associated with a reduction in 25(OH)D concentrations of 3.29 and 4.22 nmol/L for DBP-1 and DBP-2, respectively, with a gene dosage compatible with a codominant mode of inheritance (P for trend = 0.0003 and <0.0001, respectively).


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  		TABLE 2. Relation between plasma 25-hydroxyvitamin D [25(OH)D] concentrations and vitamin D binding protein (DBP) genotypes in premenopausal women

 
Vitamin D load and strength of DPB SNP effects
The amount of vitamin D needed for transportation ("vitamin D load") tends to vary with season as reflected by seasonal variations in circulating 25(OH)D. Thus, vitamin D binding protein polymorphisms could have different effects according to vitamin D load. The effect of both SNPs on 25(OH)D concentrations was more apparent when the amount of vitamin D to be transported was high (Table 3). Indeed, associations were stronger in May to October than in November to April for DBP-1 [β = –3.78 (P for trend = 0.0018) compared with β = –1.74 (P for trend = 0.21)] as well as for DBP-2 [β = –5.73 (P for trend < 0.0001) compared with β = –3.03 (P for trend = 0.037)], although the interaction was not statistically significant (P for interaction = 0.27 and 0.16 for DBP-1 and DBP-2, respectively).


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  		TABLE 3. Relation between plasma 25-hydroxyvitamin D [25(OH)D] concentrations and genotypes of vitamin D binding protein (DBP) by vitamin D load in premenopausal women

 
Contribution to variation of 25(OH)D concentrations
Relative contributions of DBP-1 or DBP-2 and other variables to the variation in plasma 25(OH)D concentrations are shown in Table 4. The adjusted model without any SNP explained 30.3% of the variation in 25(OH)D. Adding either polymorphism to this model improved its explanatory capacity to 31.2% for DBP-1 (partial r2 = 1.3%) and to 31.9% for DBP-2 (partial r2 = 2.0%), but did not substantially change the relative contribution of the other variables. DBP-1 explained as much variation in 25(OH)D concentrations as did total vitamin D intake, BMI, and education. DBP-2 explained as much variation as did total calcium intake and more than any other variable except for those related to sun exposure (ie, season and leisure-time physical activity). The importance of DBP-1 and DBP-2 as explanatory variables of the variation in 25(OH)D concentrations was even greater in May to October when the amount of vitamin D to be transported was high (partial r2 = 1.6% and 3.7% for DBP-1 and DBP-2, respectively). During this period, both SNPs explained 25(OH)D concentrations as much or even more than any other variable, except for leisure-time physical activity. In contrast, in November-April, when the amount of vitamin D to be transported was low, both SNPs explained less of the 25(OH)D variation, whereas total vitamin D intake, total calcium intake, and leisure-time physical activity became the major explanatory variables of plasma 25(OH)D.


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  		TABLE 4. Relative contribution of single nucleotide polymorphisms (SNPs) of vitamin D binding protein (DBP) genes DBP-1 or DBP-2 and other variables to the variation in plasma 25-hydroxyvitamin D [25(OH)D] concentrations globally and stratified by vitamin D load in premenopausal women

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
At the DNA level, this is the first study to our knowledge to show that plasma 25(OH)D concentrations decrease when the number of rare alleles of DBP-1 or DBP-2 increases in healthy premenopausal women. In a recent study, serum 25(OH)D concentrations in population-based postmenopausal control women also decreased significantly by Gc genotypes (defined by DBP-1 and DBP-2) (18). The DBP-2 SNP has been shown to be associated with lower 25(OH)D concentrations, but only in a group of Polish Graves’ Disease cases (16). Whereas season remains the most important explanatory variable of 25(OH)D concentrations, DBP polymorphisms explain 25(OH)D variation as much as do vitamin D intake, calcium intake, and BMI. Each DBP SNP explains even more of the 25(OH)D variation when the amount of vitamin D to be transported is high.

Our results suggest that both DBP SNPs generate functionally different proteins and that such differences affect circulating 25(OH)D concentrations. The rare allele of DBP-1 codes for the aspartic acid residue at amino acid position 416 of the DBP protein, whereas DBP-2 codes for the lysine residue at position 420, which allows for differentiation of 3 major DBP protein phenotypes (19). Being rare homozygote for both DBP-1 and DBP-2 characterize the glycosylation pattern of the protein phenotype Gc2-2, which has been shown to be associated with low mean serum DBP protein concentrations (20) and recently with low mean serum 25(OH)D concentrations in postmenopausal women (18). These results suggest that rare alleles of DBP-1 and DBP-2 are associated with lower 25(OH)D concentrations, at least in part because of the lowering effect on DBP protein concentrations. Whether the variation in DBP protein concentrations stems from different protein production or degradation rates associated with different DBP genotypes and phenotypes is unclear, but Lauridsen et al (21) suggest that, on the basis of glycosylation patterns, DBP phenotypes related to a low vitamin D concentration should be metabolized faster. This would in turn decrease the half-life of 25(OH)D, increase its conversion to inactive metabolites, and consequently reduce 25(OH)D concentrations, as shown in DBP KO mice after tritium-labeled 25(OH)D injection (22).

Few studies have examined DBP polymorphisms and risk of vitamin D–related diseases. A nonsignificant increased risk of breast cancer was associated with the DBP-2 rare homozygote (23). The rare homozygote for both DBP SNPs was associated with a reduction in postmenopausal breast cancer (18). The haplotypes of 3 SNPs on the promoter of the DBP gene suggest a nonsignificant association with prostate cancer in Americans of European descent (24). The (TAAA)n-Alu repeat polymorphisms of the DBP gene was associated with fracture risk (25, 26). DBP SNPs in linkage disequilibrium with DBP-2 were associated with bone mineral density in Japanese postmenopausal women (27). DBP-2, but not DBP-1, was associated with Graves’ disease (16) in Poland but not in nuclear families from Germany and Italy, although the DBP polymorphism (TAAA)n-Alu repeat was (28). Associations with type 2 diabetes mellitus and obesity-related traits have been observed, but the results have been inconsistent (reviewed in 7). DBP SNPs can possibly influence bioactive 25(OH)D concentrations through changes in the ratio of free to bound hormones (29), by differential affinity (30), or through effects on levels of the DBP/25(OH)D complex that can be internalized by receptor-mediated endocytosis and activate the vitamin D receptor pathway, as recently shown in mammary cells (31). In addition DBP SNPs could have effects on carcinogenesis through activation of tumoricidal macrophages and antiangiogenic effects of DBP-macrophage activating factor (reviewed in 7, 32). Overall, evidence suggests that further studies between DBP SNPs and health outcomes are needed.

The relation of both DBP SNPs to 25(OH)D seems to be more apparent when the amount of vitamin D in need of transportation is high (ie, May to October compared with November to April). Differences in 25(OH)D concentrations were also more apparent under normal rather than deficient diets in experiments with DBP knockout mice (22). Our observations appear consistent with those experimental works. Indeed, if we had assessed this association only during winter, when the vitamin D load is the lowest, no association or trend would have been detected. The effect modification by vitamin D load was not statistically significant though and should be ascertained in other studies. Nevertheless, these results stress the potential importance of considering baseline concentrations of 25(OH)D or recruitment season when studying the association of DBP SNPs with circulating 25(OH)D.

A strength of this study was that recruitment took place over one full calendar year in a relatively small geographic area over which the population experiences a large seasonal variation in sun exposure. This design facilitated the assessment of the effects of DBP genotypes on 25(OH)D concentrations, but other personal characteristics and variations in their effects according to vitamin D load could also be investigated. Leisure-time physical activity predicts greater 25(OH)D concentrations during a high vitamin D load and putatively shows that outdoor activity can improve vitamin D status, even when solar radiation and meteorological characteristics are less favorable. Even though this variable did not take into account the actual amount of outdoor exercise, level of clothing, time of day, and use of sunscreen, the results further support the idea that leisure-time physical activity is a surrogate of exposure to solar ultraviolet-B, as suggested in a recent prospective study by Giovannucci et al (33). The explanation capacity of 25(OH)D concentrations by BMI during a high vitamin D load is no longer significant during a low vitamin D load. This suggests that, in this population, possible sequestration of vitamin D into the subcutaneous fat mass reservoir (34) could be more important from early May to the end of October, when more vitamin D3 is synthesized in the skin. Total vitamin D intake only contributes to the variation in 25(OH)D concentrations under conditions of a low vitamin D load, whereas total calcium intake remains significant in both periods, which suggests that calcium's effect on 25(OH)D concentrations is independent of vitamin D intake even though both nutrient intakes are strongly correlated. Age is becoming a significant negative predictor of 25(OH)D only during high vitamin D load, which possibly reflects a reduction in 7-dehydrocholesterol (ie, precursor of vitamin D3) in the skin with aging (reviewed in 35).

Our study had some limitations. False-positive results are common in studies of the association between genetic markers and outcomes, but because we only analyzed 2 polymorphisms of the vitamin D binding protein in relation to circulating 25(OH)D concentrations, we believe that type 1 errors were not likely to explain our findings. Moreover, if we had used Bonferroni-corrected P values, the results would have remained statistically significant. Population stratification can be a concern with this type of study (36, 37), although this problem was likely not as important as anticipated in North American white populations (38–40). In our study, most of the women were from the Quebec City area, white (99.7%), and of French descent (87.7%) (15), which suggests that the associations we found were not due to population stratification. Confounding was considered; however, we do not think that this was a major concern because most key variables known to be associated with vitamin D status were accounted for in the analysis. Estrogen concentrations, which were not assessed in the present study, are known to be associated with DBP; nevertheless, adjustment for past hormone derivative use did not affect our results.

In conclusion, the number of rare alleles of DBP-1 and DBP-2 polymorphisms is inversely related to 25(OH)D concentrations in premenopausal women, and their effects on variation in 25(OH)D concentrations are comparable with those of total vitamin D intakes. DBP SNPs are inherited, which suggests that the reduction in 25(OH)D concentrations found within the rare allele carriers would persist over a lifetime. Lifelong low vitamin D concentrations may have an impact on health, and additional studies of the association between DBP polymorphisms and clinical outcomes are needed. Whether rare allele carriers of DBP rs7041 and rs4588 SNPs could benefit more or less from dietary intervention, supplementation, or sun exposure warrants additional attention.


   ACKNOWLEDGMENTS
 
The authors’ responsibilities were as follows—CD, MS, SB, MP, and JB: involved in the study design; CD, SB, and JB: supervised the data collection; and MS: performed the statistical analyses and wrote the manuscript. All authors contributed to the drafts of the manuscript and approved the final version. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication May 23, 2008. Accepted for publication November 25, 2008.




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