BackgroundPrenatal vitamin D₃ supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D₃ supplementation against offspring asthma/recurrent wheeze.MethodsWe determined the rs12936231 genotype of mother–child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC₂₀₁₀, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0–3 years between groups who received high-dose prenatal vitamin D₃ supplementation versus placebo.ResultsOffspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D₃ supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37–0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35–0.92; p=0.021 for COPSAC₂₀₁₀), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61–1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54–2.28; p=0.785 for COPSAC₂₀₁₀).ConclusionMaternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D₃ supplementation against offspring asthma/recurrent wheeze.