The Vitamin D Antenatal Asthma Trial (VDAART) established that vitamin D supplementation in pregnant women could reduce asthma/wheeze in their offspring. The genetic mechanism explaining this effect of vitamin D on the trial result was not known. Initial evidence for a genetic mechanism for the vitamin D effect came from genetic association studies. The vitamin D receptor was identified as a gene for asthma in both candidate gene studies and in GWAS. The most significant asthma GWAS locus was 17q212-21. This locus contains several genes: IKFZ3, ZBP2, ORMDL3 and GSDMB as well as STAT3 and STAT5 and IL2. This locus has been associated with multiple other autoimmune diseases. Expression of one gene in this locus, ORMDL3 has been shown in mouse studies to inhibit sphingolipid production. Sphingolipids are required for normal immune system and lung development. CHIPseq experiments identified VDR binding sites in ZBP2 and IKFZ3. Chromosomal Confirmational Capture (3C) demonstrated that these VDR binding sites acted as insulators via CTCF to suppress ORMDL3 expression, increasing sphingolipid production, and thus reducing asthma risk. In addition, enhancers in IKFZ3 led to higher levels of STAT3 and STAT5 and IL2 leading to decreased autoimmunity. These experiments strongly suggest a genetic mechanism that explains how vitamin D deficiency in pregnant women can cause abnormal fetal development and hence asthma in their offspring.