Collagen type III alpha I is a gastro-oesophageal reflux disease susceptibility gene and a male risk factor for hiatus hernia

Abstract

Background and 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 and 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 collagen type III alpha 1 (COL3A1), was identified (LOD = 3.3) in families with dominant transmission of GORD, stratified for hiatus hernia (HH). COL3A1 showed significant association with GORD in an independent paediatric trio cohort (pcorr = 0.003). The association was male specific (pcorr = 0.018). The COL3A1 association was replicated in an independent adult case control cohort (pcorr = 0.022). Moreover, male specific association to HH (pcorr = 0.019) was found for a SNP not associated to GORD. Collagen type III protein was more abundant in oesophageal biopsies from male patients with GORD (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.

Connective tissue alteration in abdominal wall hernia

“…The collagen chains are encoded by at least 17 genes. The collagen type III α1 (COL3A1) gene encodes type III collagen and might be associated with hiatus hernia formation 38 . Collagen type XXIII α1 (COL23A1) gene is probably linked to scrotal hernia development in pigs 39 .…”

Novel genetic marker for dilated end stage oesophagus and oesophageal adenocarcinoma risk?

“…The major findings of the study were that a single nucleotide polymorphism within the gene encoding for collagen type III (COL3A1) was associated with GORD in both sexes and hiatal hernia in males. In keeping with these findings, immunohistochemistry of oesophageal biopsies showed increased connective tissue abnormalities (ie, collagen type III positive staining) in GORD patients compared with asymptomatic controls 1. GORD has been defined by symptoms, endoscopy and pH monitoring data 2 3.…”

“…With interest we read the article by Asling et al ,1 entitled “Collagen type III (COL3A1) is a gastro-oesophageal reflux disease (GORD) susceptibility gene and a male risk factor for hiatus hernia”, which has been published in a recent issue of Gut . The major findings of the study were that a single nucleotide polymorphism within the gene encoding for collagen type III (COL3A1) was associated with GORD in both sexes and hiatal hernia in males.…”

“…Furthermore, the study is based on the model anatomy that the stomach commences at the level of the rise of the endoscopically visible gastric type folds 2. In keeping with this assumption, hiatal hernia has been diagnosed if gastric type folds were present above the level of the diaphragmatic impression 1 2. In contrast to that, modern histopathology and anatomy based understanding shows that what has been taken for hiatal hernia may represent “dilated end stage oesophagus” 4.…”

Hiatal hernias: a review of the pathophysiologic theories and implication for research

“…The findings showed that COL3A1 was overexpressed in families with GERD and hiatal hernia. Although it was noted to be overexpressed only in males with both GERD and hiatal hernia, the findings suggest that abnormal collagen deposition may alter the integrity of the periesophageal ligaments, thereby contributing to hiatal hernia formation [19].…”