912
11q13 Is an Allergic Risk-Locus That Increases Eoe Risk and Increases LRRC32 Expression
Monday, March 7, 2016: 2:00 PM
Room 408B (Convention Center)
Leah C. Kottyan, PhD, , , , , , , , , , , , , , , , , , , , ,
Rationale: Eosinophilic esophagitis (EoE) is a chronic, food-driven, esophageal, inflammatory allergic disease characterized by marked eosinophil accumulation. Noncoding genetic variants at 11q13 have been associated at genome-wide significance in studies of allergic sensitization, asthma, allergic rhinitis, atopic dermatitis, and EoE suggesting that these loci contains variants that participate in the allelic regulation of a molecular pathway that is central to the etiology of allergic disease.

Methods: We performed a genetic replication and fine-mapping study of the 11q13 locus in a cohort of 1118 subjects with and without EoE. We measured expression of the genes in the region in esophageal biopsies from subjects with and without EoE and in esophageal epithelial cell lines with and without IL-13 stimulation. We used electromobility shift assays to identify factors that differentially bound specific SNPs.

Results: We replicated association at 11q13 in an independent cohort (p=2.3x10-4, OR=1.27); then, we performed a meta-analysis with published results and identified a striking linkage of EoE susceptibility with 11q13 (p=1.6x10-13). LRRC32 but not EMSYis expressed in an EoE-risk genotype-dependent manner in EoE patient biopsies (p<0.05). IL-13 treatment of esophageal epithelial cells induced 3-fold increased expression of LRRC32 (p<0.0001) but not EMSY. IL-13 increased H3K27ac marks across the EoE-risk loci (p<0.001). Molecularly, one of the most highly EoE-associated and replicated variants in 11q13 with overlapping H3K27ac marks differentially bound nuclear factors from esophageal epithelial cells.

Conclusions: We identified a potential molecular mechanism for increased EoE risk at 11q13 by differential nuclear factor binding to non-coding genetic variants leading to increased expression of LRRC32.