Ergocalciferol (D2) vs. Cholecalciferol (D3) Food Fortification: Comparative Efficiency in Raising 25OHD Status & Mechanisms of Action (D2-D3 Study)

Vitamin D is the term used to describe two molecules, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). The first of these is derived by ultra-violet irradiation of the ergosterol that is widely distributed in plants and other fungi whereas cholecalciferol is formed from the action of ultra-violet irradiation on the skin. Poor vitamin D status is a very common problem in the UK. This has important health consequences (such as muscle/bone function, increasing the risk of diabetes). We urgently need to find ways of improving vitamin D intake that are acceptable as a public health strategy. Research that has just been completed by our group at the University of Surrey (Food Standards Agency funding; Project No. NO5064; £0.5M) has shown that (1) dietary intake of vitamin D is too low to have any effect on vitamin D status as there are too few foods providing a valuable natural source; (2) South Asian women are extremely vitamin D deficient; (3) Caucasians have extensive vitamin D insufficiency. There is evidence in the literature of differences in key polymorphisms of important genes that are critical to vitamin D metabolism in Asian Indian vs. Caucasians aswell as differences in key vitamin D metabolism enzymes. This requires a fuller investigation since there are differences in the availability of vitamin D2 and vitamin D3 and hence public health advice on increasing vitamin D intake (particularly with respect to the development of vitamin D rich food products) needs to confirm that either form of vitamin D is effective. Furthermore, the South Asian community are vegan/strict vegetarians (~26%) and hence the source of vitamin D3 is a problem in this group due to being derived from animals (vitamin D3 supplements come from Lanolin, which is extracted from sheep's wool.) There is currently controversy as to the effectiveness of vitamin D2 vs. D3 in raising 25HOD levels in humans. It has been assumed, largely on the strength of evidence from studies in the 1930s, that D2 and D3 were equally effective in humans but some studies show that D3 is superior to D2 in raising 25OHD levels whereas the most recently published data suggests that D2 and D3 are equally effective. This requires urgent attention. The proposed study will enable a better understanding of how comparable the two forms of vitamin D (ergocalciferol [D2] vs. cholecalciferol [D3]) are at raising vitamin D status in Caucasians and Asians and investigate the mechanisms of action with respect to any differences observed between the two vitamin D forms or between ethic groups. Mechanisms of action will focus on genetic differences aswell as differences in vitamin D metabolizing enzymes. Using a team of scientists with different expertise, our principal objectives are to: (i) compare the efficiency of 10mcg/d [400IU/d] of ergocalciferol (Vitamin D2) vs. cholecalciferol (Vitamin D3) fortification of food products in raising 25OHD levels in Asian/Caucasian women; (ii) determine which vehicle for fortification (i.e. a SOLID vs. FLUID food) with ergocalciferol (Vitamin D2) vs. cholecalciferol (Vitamin D3) is more effective in raising 25OHD levels, independent of ethnicity; (iii) investigate if 10mcg/d [400IU/d] is effective in raising wintertime 25OHD levels above 'deficiency/insufficiency' thresholds (25nmol/l and 40nmol/l respectively) in Caucasian and Asian women and whether there are any differences in ergocalciferol v. cholecalciferol fortification, independent of ethnicity; iv) investigate the mechanisms (genetic/enzymatic) for the differences observed in (i), (ii) & (iii).

Growing evidence for the positive effects of vitamin D in reducing risk from disease has increased our awareness of the need for evidence-based strategies to redress the high prevalence of low vitamin D status in the UK. This requirement has special relevance to a multi-cultural Society in which large numbers of important Minority Groups are at significantly increased risk of hypovitaminosis D. While food fortification is a sustainable solution for the prevention of vitamin D deficiency, the Food Industry needs to determine the most effective means of carriage, optimal concentration and chemical form of vitamin D if it is to maximize the effectiveness of fortification. This RCT proposal will provide much needed evidence that will; (a) directly compare the biological effects of vitamin D2 vs. vitamin D3 in fortified foods of different matrices (i.e. a solid vs. liquid food); (b) use a dose of vitamin D that is realistic and relevant to the Food Industry and the RNI (400IU); (c) examine responses in Caucasians and South Asians; (d) explore 'systems' level (genetic/enzymatic) differences in potential responses to vitamin D fortification. We hypothesise that at least some differences in the responses of participants to vitamin D fortification will be attributable to differences in gene expression. The VDR is a nuclear transcription factor which controls expression of a wide range of genes, including several that encode cytochrome P450 enzymes and cytokines. Human leukocytes are known to express the VDR-encoding gene and it is therefore envisaged that differences in vitamin D responses of individuals could be reflected by differences in leukocyte gene expression. We will determine what foods would be the best vehicles for fortification and whether there is a significant difference between the efficiency of fortification with vitamin D2 vs. vitamin D3 in their ability to raise 25OHD levels given that vitamin D intakes are insufficient in the UK throughout the year.

We have a real nutrition problem in UK Caucasians of reduced vitamin D levels and a current nutrition crisis in UK South Asians of widespread severe hypovitaminosis D. Safeguarding vitamin D levels seriously matters since it is now recognized that almost every tissue and cell in the body has a vitamin D receptor (VDR) and that for those systems to function properly, they require an adequate amount of vitamin D. The growing evidence for the positive effects of vitamin D in reducing risk from disease and all cause mortality has heightened our awareness of the need for evidence-based strategies to redress the high prevalence of low vitamin D status in the UK. From a public-health perspective, increasing dietary intake through vitamin D fortification is ideal as it is likely to reach larger proportion of the population (compared to universal recommendation for vitamin D supplementation). This proposal will significantly benefit the Food Industry by providing them with key information on the most effective means of fortification of products with vitamin D, including data on carriage, optimal concentration and chemical form of vitamin D. This will allow maximization of the effectiveness of food fortification in the future. This proposal will also significantly benefit Caucasian and Asian communities since it will provide them with examples of 'real' foods that can be consumed and which are able to increase their vitamin D levels. This study will be particularly of benefit to our multi-cultural Society in which large numbers of important Minority Groups are so at risk of low vitamin D status.. By exploring both SOLID and LIQUID food vehicles, we can determine potential vehicles for fortification and plan further for future products. For example, if vitamin D could be added to Chapati Flour, this would be likely to have a very significant impact on raising vitamin D levels in Asian communities. This study will also be of great benefit to vegans/vegetarians who find the vitamin D3 form unacceptable for consumption (as supplements or in food fortification) due to it animal origins. This proposal will ofcourse also be of great benefit to the scientific community by exploring the vitamin D2 vs. vitamin D3 food fortification comparisons for the first time in the same study design aswell as the 'systems' level differences (genetic/enzymatic) in potential responses to vitamin D fortification, independent of ethnicity. We will ensure that the results of our study are widely disseminated - at the scientific level through peer-reviewed publications, at the food industry level through published literature in technical documents but also at the population level through our established Caucasian and Asian networks, community talks and community publications (such as health magazines, newspapers and ethnic group newsletters).