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 =0.049 and child pinteraction =0.001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), p=0.006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), p=0.58 and 0.94 (0.47-1.89), p=0.87, 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 ≥0.17. 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.