Vitamin D related genes in lung development and asthma pathogenesis

abstract: ...Background Poor maternal vitamin D intake is a risk factor for subsequent childhood asthma, suggesting that in utero changes related to vitamin D responsive genes might play a crucial role in later disease susceptibility. We hypothesized that vitamin D pathway genes are developmentally active in the fetal lung and that these developmental genes would be associated with asthma susceptibility and regulation in asthma. Methods Vitamin D pathway genes were derived from PubMed and Gene Ontology surveys. Principal component analysis was used to identify characteristic lung development genes. Results Vitamin D regulated genes were markedly over-represented in normal human (odds ratio OR 2.15, 95% confidence interval CI: 1.69-2.74) and mouse (OR 2.68, 95% CI: 2.12-3.39) developing lung transcriptomes. 38 vitamin D pathway genes were in both developing lung transcriptomes with >63% of genes more highly expressed in the later than earlier stages of development. In immortalized B-cells derived from 95 asthmatics and their unaffected siblings, 12 of the 38 (31.6%) vitamin D pathway lung development genes were significantly differentially expressed (OR 3.00, 95% CI: 1.43-6.21), whereas 11 (29%) genes were significantly differentially expressed in 43 control versus vitamin D treated immortalized B-cells from Childhood Asthma Management Program subjects (OR 2.62, 95% CI: 1.22-5.50). 4 genes, LAMP3 , PIP5K1B , SCARB2 and TXNIP were identified in both groups; each displays significant biologic plausibility for a role in asthma. Conclusions Our findings demonstrate a significant association between early lung development and asthmarelated phenotypes for vitamin D pathway genes, supporting a genomic mechanistic basis for the epidemiologic observations relating maternal vitamin D intake and childhood asthma susceptibility.

... stages of development. In immortalized B-cells derived from 95 asthmatics and their unaffected siblings, 12 of the 38 (31.6%) vitamin D pathway lung development genes were significantly differentially expressed (OR 3.00, 95% CI: 1.43-6.21), whereas 11 (29%) genes were significantly differentially expressed in 43 control versus vitamin D treated immortalized B-cells from Childhood Asthma Management Program subjects (OR 2.62, 95% CI: 1.22-5.50). 4 genes, LAMP3 , PIP5K1B , SCARB2 and TXNIP were

... 0.032 -0.115 8395 PIP5K1B - U -0.239 0.149 0.107 9476 NAPSA - U -0.032 0.388 0.036 10561 IFI44 - U -0.183 -0.098 -0.326 10628 TXNIP S - -0.211 -0.360 -0.151 27074 LAMP3 - U 0.127 0.080 0.097 54541 DDIT4 - U 0.080 -0.018 0.456 64135 IFIH1 - U 0.178 0.058 -0.243 79161 TMEM243 - U 0.000 0.054 0.168 79805 VASH2 - U 0.090 0.302 0.179 Bold log2 values indicate statistical significance. For the pediatric asthma sibling pair study [ 21 ], 2,697 genes (of 20,188 unique genes measured) were differentially expressed between LCLs of 95 affected versus unaffected siblings pairs at p<0.05. There was a significant overlap of 86 genes between this 2,697-gene set and the VDRGS (OR 1.77, 95% CI: 1.38-2.27). Focusing on the 38 common VDRGS-DLCGS genes, 12 (31%) were significantly differentially expressed between unaffected-affected siblings: CD44, HLA-DRB1, IFIH1, IGF1*, LAMP3, LY75, MYC, PIP5K1B*, SCARB2*, SFRP1 , TXNIP* and TYMS* , where* indicates under expression in the affected relative to the unaffected

... genes (of 24,960 unique genes measured) were differentially expressed between LCLs of vitamin D versus control treatment at p<0.05. There was a significant overlap of 161 genes between this 3,368-gene set and the VDRGS (OR 4.30, 95% CI: 3.50-5.29) (Figure 3 ). Focusing on the 38 common VDRGS-DLCGS genes, 11 (22%) were significantly differentially expressed between control-vitamin D treatment: CAV1*, CD69, IFI44*, LAMP3, NAPSA, PIP5K1B, PRNP, SAT1, SCARB2*, TXNIP* and VASH2, where* indicates under

... development are also differentially expressed in LCLs derived from asthmatic children as compared to non-asthmatic sibling controls. Overall, vitamin D lung developmental genes were three times as likely to be differentially expressed in these asthmatics, when compared to non-vitamin D genes. Finally, we noted that, of the 12 vitamin D lung developmental genes transcriptomically related to asthma susceptibility, 4 LAMP1, PIP5K1B, SCARB2 , and TXNIP were significantly differentially expressed upon

... pathway genes involved in the immune mediation of asthma. Given their fetal lung and subsequent immune cell localization, it is possible that the remainder of the developmental 12 vitamin D genes that are differentially expressed in asthma may influence asthma in cells specific to the lung, such as epithelial or airway smooth muscle cells. As mentioned, 4 of the developmental genes: LAMP1, PIP5K1B, SCARB2 and TXNIP , were differentially expressed in both asthma and upon stimulation of immortalized B

... maturation [ 41 ] and has been implicated in the pathogenesis of psoriasis vulgaris [ 42 ]. PIP5K1B regulates calcium signaling in mast cells[ 43 ]. Both the dendritic cell and the mast cell are key regulators in the initiation of the asthmatic inflammatory response. Furthermore, the SNP rs975645 of PIP5K1B2 was found to be associated with asthma under a dominant genetic model in our previous CAMP study (p=0.004) [ 32 ]. In lieu of direct actions on inflammatory cells, SCAR2B appears to modulate the

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Gene: PIP5K1B - phosphatidylinositol-4-phosphate 5-kinase, type I, beta - (NCBI)

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