Collagen type III alpha I is a gastro-oesophageal reflux disease susceptibility gene and a male risk factor for hiatus hernia.
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.
Asling
B
B
AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden. Bengt.asling@astrazeneca.com
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
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
C439971:COL3A1 protein, human; D024061:Collagen Type III