Responses of Total and Bioavailable 25‐Hydroxyvitamin D and Factors Modifying the Responses: A Randomized, Placebo‐Controlled Trial of Vitamin D3 Supplementation in an Asian Population

Abstract

Vitamin D deficiency, defined as circulating 25‐hydroxyvitamin D [25(OH)D<50 nmol/L], is a common nutrition problem globally. Ethnic differences were noticed in vitamin D status and related health outcomes. However, little is known about how genetic and other factors influence vitamin D metabolism in Asians despite of having the world largest population. Recently, we have conducted two randomized clinical trials. One of them (n=76) was a 5‐arm, dose‐response study to evaluate effects of daily administration from 400 IU (Chinese Recommended Dietary Allowance) to 2000 IU (Chinese tolerable Upper Intake Level) of vitamin D3 on serum 25(OH)D levels. After 16 week, only 80% of participants in 2000 IU group achieved the Institute of Medicine targeted level of 50 nmol/L. In another recent 2‐arm trial, we further investigated: 1) responses of total and bioavailable 25(OH)D, defined as fraction of circulating 25(OH)D unbound to vitamin D binding protein (VDBP); and 2) effects of personal and genetic factors on the responses. A total of 448 participants with vitamin D deficiency were randomly assigned to placebo or treatment arm (2000 IU/d vitamin D3). Serum 25(OH)D, VDBP, iPTH, calcium were measured at week 0, 10 and 20. Bioavailable 25(OH)D was calculated by validated formulas. Six single nucleotide polymorphisms in vitamin D pathway genes (GC, VDR, DHCR7, CYP2R1, CYP24A1) were genotyped. After 20 weeks, the mean (SD) of total 25(OH)D increased from 32.3(8.7) nmol/L and 32.9(8.9) nmol/L to 36.3(9.8) nmol/L and 67.3(23.1) nmol/L; while the mean bioavailable 25(OH)D increased from 7.0(3.5) nmol/L and 7.3(4.1) nmol/L to 7.6(4.1) nmol/L and 14.7(8.3) nmol/L in placebo and treatment arm, respectively (all Pbetweengroups<0.001). Approximately 75% of participants in treatment arm achieved 25(OH)D of 50 nmol/L at week 20. Mean (SE) VDBP levels at baseline were 165.3(4.3) ug/ml and remained steady through the trial. The responses of total or bioavailable 25(OH)D to vitamin D3 supplement were modified by variants in GC and VDR (P≤0.03). Interestingly, there was significant interaction between GC rs7041 genotypes and treatment in bioavailable 25(OH)D response (Pinteraction<0.001), but not in total 25(OH)D response. Other determinants for the responses of total and bioavailable 25(OH)D included their baseline values, gender and BMI [only total 25(OH)D response]. Compared with previously reported VDBP level (337±5 ug/ml) in white American, our participants showed substantially lower VDBP levels, which is apparently attributed to higher prevalence of GC rs7041‐T, thereby raised bioavailable 25(OH)D levels. To our best knowledge, this study is the first trial determining the responses of total and bioavailable 25(OH)D and modifying factors on the responses. Findings of unique combinations of genetic polymorphisms and VDBP profile in Chinese, implicates that different cut‐off points might be needed to define vitamin D status and also to modify current recommendation for Asians.Support or Funding InformationThis study was supported by Ministry of Science and Technology of China [2013BAI04B03], and the National Natural Science Foundation of China [81170734, 81321062].