Genotyping could help identify people who would most benefit from vitamin D supplements to prevent their progression to diabetes, further analysis of a clinical trial suggests.
The genetic association study indicated that individuals with glycemic indicators of prediabetes could benefit from supplementation with 4000 IU/d of vitamin D3 if they carried specific genetic polymorphisms.
Two genotypes of the ApaI vitamin D receptor polymorphism (VDR) were linked to a risk reduction when these vitamin supplements were taken compared with placebo, according to the report in JAMA Open.
“Our exploratory findings, if confirmed, hold promise for high-dose vitamin D3 as a targeted, personalized approach to reducing the risk of type 2 diabetes among selected adults with prediabetes,” reported Bess Dawson-Hughes, MD, from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, and co-workers.
“The magnitude of the observed risk reduction among participants with AC and CC alleles of the ApaI polymorphism, if confirmed in an independent clinical trial, would have clinical implications for the management of prediabetes.”
There are four major polymorphisms in the vitamin D receptor: FokI, BsmI, ApaI, and TaqI. While the FokI polymorphism produces a shorter vitamin D receptor with enhanced transcriptional activity, the BsmI, ApaI, and TaqI polymorphisms influence mRNA stability, posttranscriptional regulation, and translational efficiency.
ApaI is strongly associated with metabolic syndrome and obesity, which are both major risk factors for type 2 diabetes.
In an extended analysis of the Vitamin D and Type 2 Diabetes (D2d) trial, researchers examined whether VDR gene variants modified the results of the trial.
The primary outcome of the original trial, conducted in people who achieved at least two of the three glycemic criteria for prediabetes, did not reach statistical significance in the intention-to-treat analysis. However, further examination revealed that the effect of vitamin D3 depended on the achieved intratrial serum 25-hydroxyvitamin D (25[OH]D) levels.
Dawson-Hughes and team therefore examined common VDR polymorphisms in the D2d trial to see whether these polymorphisms were associated with reduced diabetes risk among participants who achieved higher intratrial mean 25(OH)D level, in a discovery-level analysis.
They then conducted a test phase to determine whether participants’ VDR genetic profile modified the response to vitamin D3 supplementation compared with placebo.
Among 2098 participants in the D2d trial, the 618 carrying the AA alleles experienced no reduction in risk of progression to type 2 diabetes either when achieving higher intratrial 25(OH)D concentrations or when using vitamin D3 4000 IUs per day for a median of 2.5 years after adjusting for race, sex, and body mass index, among other variables.
However, the 1480 participants with ApaI AC and CC genotypes—representing 71% of the study population—had a progressively lower risk of type 2 diabetes at intratrial 25(OH)D levels of 40 ng/ml or higher.
Participants with these genotypes had a 19% reduction in the risk of progressing to type 2 diabetes over the same period (Hazard ratio=0.81).
“If confirmed, a 19% risk reduction in conversion to type 2 diabetes with vitamin D3 supplementation would not be trivial,” the authors concluded, noting that assessment of a single VDR polymorphism is inexpensive and now widely available.
In a Commentary article accompanying the study, Michael Holick, PhD, and Arash Shirvani, PhD, both from Boston University, added: “The enormity of the disease burden of diabetes worldwide and the confirmation that vitamin D supplementation of 4000 IUs per day markedly reduces risk of developing it should be a wake-up call and the impetus for health organizations to develop strategies to improve vitamin D status for children and adults with food fortification programs, implementation of supplementation, and sensible sun exposure recommendations for those who are at risk.”
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