Vitamin D receptor genotype may identify prediabetes patients who respond to high-dose vitamin D
A JAMA Network Open study found high-dose vitamin D may reduce progression from prediabetes to type 2 diabetes in people with certain vitamin D receptor genotypes. In participants with ApaI CC or AC alleles, risk fell 19% versus placebo, while no reduction was seen in those with ApaI AA alleles.
High-dose vitamin D may delay or prevent the progression of prediabetes to type 2 diabetes, but only in people with certain polymorphisms in the vitamin D receptor, new research suggested. In participants with ApaI CC and AC alleles, vitamin D reduced the risk of developing diabetes by 19% compared with placebo, while among participants with ApaI AA alleles, vitamin D did not appear to reduce the risk. The study was published in JAMA Network Open.
Researchers analyzed data from adults with prediabetes who were enrolled in the earlier Vitamin D and Type 2 Diabetes (D2d) trial, with available intratrial 25(OH)D levels and genotyping. In the initial study, participants were randomly assigned to receive 4000 IU/d of vitamin D3 or a placebo daily for a median of 2.5 years. Although vitamin D led to a reduction in progression from prediabetes to type 2 diabetes, the finding failed to reach statistical significance in the intent-to-treat analysis (hazard ratio [HR], 0.88; 95% CI, 0.75-1.04).
In the genetic association study, researchers evaluated whether three common polymorphisms (ApaI, BsmI, and FokI) in the vitamin D receptor were associated with reduced diabetes risk among participants (n = 1903) who achieved higher intratrial mean 25(OH)D levels. This aspect of the study was called the discovery phase. The test phase then investigated whether participants’ vitamin D receptor genetic profile modified the response to vitamin D3 supplementation compared with placebo.
In the discovery phase, participants with the ApaI CC genotype had HRs of 0.29 (95% CI, 0.13-0.65) for incident diabetes at 25(OH)D levels of 40-50 ng/mL and 0.17 (95% CI, 0.07-0.43) at ≥ 50 ng/mL. Among those with the AC genotype, HRs for incident diabetes were 0.51 (95% CI, 0.30-0.86) and 0.26 (95% CI, 0.14-0.48), respectively. These groups were classified as responders, while participants with the AA genotype showed no risk reduction and were considered nonresponders.
A similar pattern was observed for BsmI, but results for FokI were less consistent, so this polymorphism was not analyzed further. The lack of risk reduction among ApaI AA carriers, along with the observation that most individuals with the nonresponsive BsmI TT genotype also carried ApaI AA, suggested that ApaI genotyping alone might be sufficient to identify individuals with prediabetes who would be more or less likely to respond to high-dose vitamin D3 supplementation.
Researchers then analyzed participants with complete ApaI genotype data (n = 2098; mean [standard deviation] age, 60.2 [9.9] years; 55.7% men), stratifying them solely by ApaI genotype into two groups: 29.5% were classified as proposed nonresponders and 70.5% were classified as proposed responders. The groups were generally well balanced at baseline, achieving similar intratrial serum 25(OH)D concentrations.
In participants with ApaI CC and AC alleles, vitamin D reduced the risk of developing diabetes by 19% (HR, 0.81; 95% CI, 0.66-0.99) compared with placebo, while among participants with ApaI AA alleles, vitamin D did not appear to reduce the risk (HR, 1.02; 95% CI, 0.72-1.44). The study was too small to examine the association between ApaI alleles and treatment response within individual groups by race and ethnicity, and did not address the mechanisms by which ApaI genotypes are associated with vitamin D response.