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|Title:||Collagen type III alpha 1 is a gastro-oesophageal reflux disease susceptibility gene and a male risk factor for hiatus hernia|
|Citation:||Gut, 2009; 58(8):1063-1069|
|Publisher:||British Med Journal Publ Group|
|B Åsling, J Jirholt, P Hammond, M Knutsson, A Walentinsson, G Davidson, L Agreus, A Lehmann, M Lagerström-Fermer|
|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.|
|Keywords:||Esophagus; Humans; Gastroesophageal Reflux; Hernia, Hiatal; Genetic Predisposition to Disease; Collagen Type III; Risk Factors; Case-Control Studies; Chromosome Mapping; DNA Mutational Analysis; Sex Factors; Genotype; Polymorphism, Single Nucleotide; Adolescent; Child; Child, Preschool; Infant; Female; Male|
|Description:||Published Online First 26 April 2009|
|Rights:||Copyright © 2009 BMJ Publishing Group Ltd & British Society of Gastroenterology.|
|Appears in Collections:||Paediatrics publications|
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