Vitamin D receptor polymorphisms and the effect of vitamin D supplementation on diabetes risk among adults with prediabetes

Authors: DAWSON-HUGHES, BESS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HUGGINS, GORDON - Tufts Medical Center; NELSON, JASON - Tufts Medical Center; VICKERY, ELLEN - Tufts Medical Center; POWERS, SARAH - Tufts Medical Center; PITTAS, ANASTASSIOS - Tufts Medical Center

Submitted to: Journal of the American Medical Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/10/2026
Publication Date: 4/23/2026
Citation: Dawson-Hughes B, Huggins GS, Nelson J, Vickery E, Powers SN, Pittas AG. Vitamin D receptor polymorphisms and the effect of vitamin D supplementation on diabetes risk among adults with prediabetes. JAMA Netw Open. 2026;9(4):e267332. https://doi.org/10.1001/jamanetworkopen.2026.7332.
DOI: https://doi.org/10.1001/jamanetworkopen.2026.7332

Interpretive Summary: In the recently completed D2d clinical trial in adults at high risk of developing type two diabetes, there was a trend toward diabetes risk reduction in those taking 4000 IU of vitamin D daily, compared with placebo over a 2.5-year period. It is not known whether there is a subset of adults who are more likely than others to benefit from the supplementation. We assessed whether common variants in the vitamin D receptor influenced the impact of supplementation on the risk of diabetes in 2,098 participants in D2d. We found that participants with a specific alteration in the vitamin D receptor were unresponsive to supplementation, whereas in the 70% of participants without this alteration, 4000 IU of vitamin daily significantly lowered risk of developing diabetes by 19%. If confirmed, this would support the use of genotyping to identify individuals likely to benefit from treatment with high dose vitamin D to reduce risk of diabetes.

Technical Abstract: Importance: Achieving and maintaining a serum 25-hydroxyvitamin D [25(OH)D] level = 40 ng/mL, when compared with levels generally considered sufficient (20 to 30 ng/ml), may lower diabetes risk in adults with prediabetes. It is not known whether there is a subset of adults with prediabetes who are likely to benefit from higher 25(OH)D levels to target for vitamin D supplementation to reduce their risk of diabetes. Objective: To assess whether common polymorphisms of the vitamin D receptor (VDR) influence the impact of supplementation with 4,000 IU/day on the risk of diabetes in adults with prediabetes Design: A VDR genotype analysis of 3 common polymorphisms: ApaI, BsmI, and FokI Setting: The Vitamin D and Type 2 Diabetes (D2d) clinical trial Participants: Participants with available DNA (N=2,098) Exposures: 4,000 IU per day of vitamin D vs placebo for a median of 2.5 years Main Outcomes and Measures: In the Discovery phase analysis, we examined the risk of diabetes in adults at different achieved intratrial mean 25(OH)D levels in relation to the three common VDR polymorphisms. This was followed by a Test phase analysis examining the response to vitamin D supplementation on incident diabetes according to the ApaI genotypes. Results: In models adjusted for study site, race, sex, age, body mass index, usual physical activity, and statin use, and intra-trial weight change, participants with ApaI AA alleles did not respond to treatment with vitamin D (HR 1.02 [0.72, 1.44]; N=618). In contrast, those with AC and CC genotypes had a 19% decrease in the risk of diabetes (HR 0.81 [0.66, 0.99]; N=1,480). Conclusions and relevance: Vitamin D risk reduction following supplementation with 4,000 IU/d of vitamin D was restricted to participants who had specific alleles of the ApaI polymorphism, AC and CC. If confirmed, this would support the use of ApaI genotyping to identify individuals likely to benefit from treatment with high-dose vitamin D to reduce the risk of diabetes.