Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Abstract

Background & aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P_BONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P_BONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals.

Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Keywords: Barrett’s esophagus; Genome-Wide Association Study; Interaction; Sex Difference.

Figure 1.

Manhattan plots of the genome-wide meta-analysis on the risk of BE and EA. (A) males; (B) females; (C) 2-df joint meta-analysis of SNP main and SNP-by-sex interaction. The axis shows −log10 P values. The red lines represent the genome-wide threshold for statistical significance (P < 5 × 10⁻⁸). The blue lines represent suggestive significance (P < 1 × 10⁻⁵).

Figure 2.

Regional plots of the novel SNP identified. Results (−log10 P) are shown for SNPs in the region flanking 400 kb on either side of SNP. The marker SNP is shown in purple and the r² values of the rest of the SNPs are indicated by different colors. The genes within the region of interest are annotated, with arrows indicating transcription direction. (A) rs35827298; (B) rs13259457; (C) rs17321041.