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Gut 2009;58:1063-1069 doi:10.1136/gut.2008.167353
  • Oesophagus

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

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  1. B Åsling1,
  2. J Jirholt1,
  3. P Hammond2,
  4. M Knutsson1,
  5. A Walentinsson1,
  6. G Davidson2,
  7. L Agreus3,
  8. A Lehmann1,
  9. M Lagerström-Fermer1
  1. 1
    AstraZeneca R&D, Mölndal, Sweden
  2. 2
    Women’s & Children’s Hospital, Gastroenterology Unit, North Adelaide, Australia
  3. 3
    Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden
  1. Dr B Åsling, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden; Bengt.asling{at}astrazeneca.com
  • Revised 13 March 2009
  • Accepted 31 March 2009
  • Published Online First 26 April 2009

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.

Footnotes

  • Competing interests: None.

  • Funding: This work was funded by AstraZeneca R&D, Mölndal, Sweden.

  • Ethics approval: Informed consent was obtained before enrolment. All data and DNA/tissue samples were coded. Ethics approval was obtained for all patient collections. Extended Kalixanda was approved by Umeå University with reference number 321/03, diary nr 03-285. Families and Trios was approved by WCH Research Ethics Committee with reference numbers REC1262/11/2004 and REC1340/6/2005. EsoNerd was approved with reference number S 499-3. Decision 2003-11-18 Studiekod: CPM-ESEP-0002.

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