Vitamin D related genes in lung development and asthma pathogenesis
1 Children’s Hospital Informatics Program, Boston Children’s Hospital, 320 Longwood Avenue, Boston, MA 02115, USA
2 Harvard Medical School, Boston, MA, USA
3 Channing Division of Network Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
4 Pulmonary Division, Brigham and Women’s Hospital, Boston, MA, USA
5 Children’s Mercy Hospital, Kansas City, MO, USA
6 Partners Health Care Center for Personalized Genetic Medicine, Boston, MA, USA
7 University of Rochester Medical Center, Rochester, NY, USA
8 Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
9 Division of Pediatric Clinical Pharmacology and Medical Toxicology, Children’s Mercy Hospital and Clinics, 2401 Gilham Road, Kansas City, MO 64108, USA
10 Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
BMC Medical Genomics 2013, 6:47 doi:10.1186/1755-8794-6-47Published: 5 November 2013
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.
Vitamin D pathway genes were derived from PubMed and Gene Ontology surveys. Principal component analysis was used to identify characteristic lung development genes.
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.
Our findings demonstrate a significant association between early lung development and asthma–related phenotypes for vitamin D pathway genes, supporting a genomic mechanistic basis for the epidemiologic observations relating maternal vitamin D intake and childhood asthma susceptibility.