Background and 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 three separate studies and then used fixed-effects meta-analysis to provide summary estimates for > 9 million variants for males and females. A series of downstream analyses were conducted separately in males and females to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.
Results: We included 6,758 male BE/EA cases, 7,489 male controls, 1,670 female BE/EA cases and 6,174 female controls. Meta-analysis of sex-specific GWAS identified three novel independent genome-wide significant loci for BE/EA, including one variant at chromosome 12p12.3 (rs35827298, MGST1-LMO3, P = 1.28×10-8) detected in males only, and two variants at chromosome 8p (rs13259457, PRSS55-RP1L1, P = 6.65×10-9, and rs17321041, DPYSL2, P = 4.98×10-8) detected in females only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in males and obesity in females.
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.
|Publication status||Accepted/In press - 16 Mar 2020|
- esophageal adenocarcinoma
- Barrett’s esophagus
- sex difference
- genome-wide association study