Abstract

Background & objectives: Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal disorder with a genetic component. Our aim was to identify genetic factors associated with GORD.

Patients & methods: Four separate patient cohorts were analysed using a step-wise approach. (1) Whole genome linkage analysis was performed in 36 families. (2) Candidate genes were tested for GORD association in a trio cohort. (3) Genetic association was replicated in a case-control cohort. We also investigated genetic association to hiatus hernia (HH). (4) Protein expression was analysed in oesophageal biopsies.

Results: A region on chromosome 2, containing COL3A1, was identified (LOD=3.3) in families with dominant transmission of GORD, stratified for HH. COL3A1 showed significant association with GORD in an independent paediatric trio cohort (P_corr=0.003). The association was male specific (P_corr=0.018). The COL3A1 association was replicated in an independent adult case control cohort (P_corr=0.022). Moreover, male specific association to HH (P_corr=0.019) was found for a SNP not associated to GORD. Collagen type III protein was more abundant in oesophageal biopsies from male GORD patients (p=0.03).

Conclusion: COL3A1 is a disease associated gene in both paediatric and adult GORD. Furthermore, we show that COL3A1 is genetically associated with HH in adult males. The GORD and HH associated alleles are different, indicating two separate mechanisms leading to disease. Our data provides new insight into GORD aetiology, identifying a connective tissue component and indicating a tissue remodelling mechanism in GORD. Our results implicate gender differences in the genetic risk for both for GORD and HH.