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

Full 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 (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 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.

Author information

Author/s: Asling, B (B); Jirholt, J (J); Hammond, P (P); Knutsson, M (M); Walentinsson, A (A); Davidson, G (G); Agreus, L (L); Lehmann, A (A); Lagerström-Fermer, M (M);

Affiliation: AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden. Bengt.asling(-atsign-)astrazeneca.com

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Gut (Gut), published in England. (Language: eng)

Reference: 2009-Aug; vol 58 (issue 8) : pp 1063-9

Dates: Created 2009/07/13; Completed 2009/09/03;

PMID: 19398442, status: MEDLINE (last retrieved date: 9/4/2009)

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