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Methylation Sites Associated with Alteration in Gene Expression in the ZPBP2/GSDMB/ORMDL3 Locus
Monday, March 7, 2016
South Exhibit Hall H (Convention Center)
Parul H. Kothari, MD, PhD, Weiliang Qiu, PhD, Damien C. Croteau-Chonka, PhD, Vincent J. Carey, PhD, Benjamin A. Raby, MD MPH
Rationale: A regulatory haplotype spanning ORMDL3, GSDMB, and ZPBP2 is the most reproducible genetic locus for asthma. Though small studies have suggested potential epigenetic regulation, the contribution of CpG methylation to these genes’ expression has not been studied at a population level. 

Methods:  We analyzed 296 subjects from Asthma BRIDGE with whole blood Illumina HumanMethylation450 and HumanHT-12 expression data. Data from available expression probes for ZPBP2 (3 probes), GSDMB (3), and ORMDL3 (1), and all variable methylation sites within 50 kb of each gene were considered. A generalized linear model was applied to test the association of methylation on gene expression, adjusting for potential confounders. 

Results:  Of 330 probe-site pairs tested, 30 were significant at a false discovery rate (FDR) < 0.05. Significant associations for GSDMB were observed with 13 different methylation sites, of which 10 were also associated with ORMDL3 expression, with similar directions of effect. No significant associations were observed for ZPBP2. Among the CpG marks most strongly associated with both GSMDB and ORMDL3 was cg10057218 (FDR = 0.004 and 0.01, respectively). Methylation at this site was inversely correlated with both genes’ expression, and was also strongly associated with a nearby SNP, rs8067378 (FDR = 0.003) – one of the regulatory variants most strongly associated with asthma in prior genome-wide association studies.

Conclusions: Numerous local DNA methylation sites are associated with GSDMB and ORMDL3 gene expression, and with a known asthma-susceptibility SNP. These findings further illustrate the complex interplay of genetic and epigenetic alterations in the pathogenesis of asthma.