title: Collagen type III alpha I is a gastro-oesophageal reflux disease susceptibility gene and a male risk factor for hiatus hernia.
abstract: OBJECTIVE
  Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal disorder with a genetic component. Our aim was to identify genetic factors associated with GORD.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden. Bengt.asling@astrazeneca.com
authors.forename: B
authors.initials: B
authors.lastname: Asling
authors.forename: J
authors.initials: J
authors.lastname: Jirholt
authors.forename: P
authors.initials: P
authors.lastname: Hammond
authors.forename: M
authors.initials: M
authors.lastname: Knutsson
authors.forename: A
authors.initials: A
authors.lastname: Walentinsson
authors.forename: G
authors.initials: G
authors.lastname: Davidson
authors.forename: L
authors.initials: L
authors.lastname: Agreus
authors.forename: A
authors.initials: A
authors.lastname: Lehmann
authors.forename: M
authors.initials: M
authors.lastname: Lagerström-Fermer
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D024061:Collagen Type III / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004947:Esophagus / Q000378:metabolism; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006551:Hernia, Hiatal / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors
chemical_list: C439971:COL3A1 protein, human; D024061:Collagen Type III