X chromosomal linkage to eosinophilic esophagitis susceptibility
Monday, March 5, 2018
South Hall A2 (Convention Center)
Leah C Kottyan, PhD, Avery Maddox, Kate Hoffman, Leanne Ray, Carmey Forney, Michael Eby, Melissa K Mingler, MS, MBA, Kenneth Kaufman, PhD, Phillip Dexheimer, Nina Lukac, Julie M Caldwell, PhD, Mark Rochman, PhD, Tetsuo Shoda, MD, PhD, Ting Wen, PhD, Justin C. Wheeler, MD, Simon P. Hogan, PhD, Vincent A Mukkada, MD, Philip E Putnam, MD, Juan Pablo Abonia, MD, Robert M. Genta, PhD, Lisa J. Martin, PhD, Evan S. Dellon, MD MPH, Marc E Rothenberg, MD PhD FAAAAI
RATIONALE: Eosinophilic esophagitis (EoE) is a chronic allergic disease with a marked difference in sex distribution; ~65% of patients are male. Prior genome-wide association studies (GWAS) have identified replicated EoE-risk loci but these analyses did not assess non-autosomal genomic loci.

METHODS: We assessed 14,481 subjects with esophageal eosinophilia living in 48 contiguous states and found a male predominance regardless of region (61.4%-66.4%), population density (63.6%-64.8%), or age (59.2%-67.4%) collectively emphasizing consistent sex differences. We performed an association study of the X and Y chromosomes, including the pseudoautosomal region, data in 732 cases and 9288 controls from two independent cohorts. High-depth RNA sequencing and the eosinophil diagnostic panel were used to measure gene expression of 20 biopsies from well-matched male and female children with and without EoE.

RESULTS: We identified a new EoE risk locus at Xq28 associated with increased EoE risk in both males and females and encoding the genes VMA21 and GPR50 (pcombined=2.11x10-10, Odds Ratio (OR)combined=1.31; pmale=2.4x10-8, ORmale=1.30 and pfemale=0.002, ORfemale=1.35). Sex-specific analyses of common variants did not reveal non-autosomal genetic variation sufficient to explain the observed male-predominated disease. Gene expression from esophageal biopsies was largely similar across sex with non-statistically significant trends towards sex-dependent expression of some members of the EoE-transcriptome. A subset of 20 genes expressed from the X and Y chromosomes were expressed in a sex-dependent manner (fold-change>2; pcorrected<0.05).

CONCLUSIONS: Altogether, our work establishes a new EoE risk locus at Xq28 and was unable to identify evidence that male predominance is dictated by non-autosomal genetic variants.