Oesophagus

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

B Åsling¹, J Jirholt¹, P Hammond², M Knutsson¹, A Walentinsson¹, G Davidson², L Agreus³, A Lehmann¹, M Lagerström-Fermer¹

¹ AstraZeneca R&D, Mölndal, Sweden
² Women’s & Children’s Hospital, Gastroenterology Unit, North Adelaide, Australia
³ Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden

Dr B Åsling, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden; Bengt.asling{at}astrazeneca.com

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.

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