High‐dose vitamin D during pregnancy and pathway gene polymorphisms in prevention of offspring persistent wheeze

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.