<p class="first" id="P1">Esophageal adenocarcinoma (EA) incidence has risen sharply
in Western countries over
recent decades. Local and systemic inflammation, operating downstream of disease-associated
exposures, is considered an important contributor to EA pathogenesis. Several risk
factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including
symptomatic reflux, obesity, and smoking. The role of inherited genetic susceptibility
remains an area of active investigation. To explore whether germline variation related
to inflammatory processes influences susceptibility to BE/EA, we used data from a
genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207
controls. Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449
genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative
stress, human leukocyte antigen, and NFκB. A principal components-based analytic framework
was employed to evaluate pathway-level and gene-level associations with disease risk.
We identified a significant signal for the COX pathway in relation to BE risk (P=0.0059,
FDR q=0.03), and in gene-level analyses found an association with
<i>MGST1</i> (microsomal glutathione-S-transferase 1; P=0.0005, q=0.005). Assessment
of 36
<i>MGST1</i> SNPs identified 14 variants associated with elevated BE risk (q<0.05).
Of these,
four were subsequently confirmed (P<5.5 × 10
<sup>−5</sup>) in a meta-analysis encompassing an independent set of 1,851 BE cases
and 3,496 controls.
Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar
elevations in EA risk. This study provides the most comprehensive evaluation of inflammation-related
germline variation in relation to risk of BE/EA, and suggests that variants in
<i>MGST1</i> influence disease susceptibility.
</p>