BACKGROUND: Randomized controlled trials (RCTs) suggest a protective effect of high-dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs.

METHODS: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010 ) RCT, we analyzed the effect of high-dose vitamin D during pregnancy on the risk of persistent wheeze age 0-3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART).

RESULTS: In COPSAC2010 , VDR SNP rs1544410 influenced the effect of high-dose vitamin D: maternal Pinteraction = .049 and child Pinteraction = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), P = .58 and 0.94 (0.47-1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC2010 or VDAART: all Pinteraction ≥ .17.

CONCLUSIONS: We found that the effect of high-dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not VDAART, which may be due to population differences.