Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease.
Linkage analyses have implicated chromosome 7p21.3 as a susceptibility region for inflammatory bowel disease (IBD). Recently, the mouse phenotype with diarrhea and goblet cell dysfunction caused by anterior gradient protein 2 dysfunction was reported (European patent WO2004056858). The genes encoding for the human homologues AGR2 and AGR3 are localized on chromosome 7p21.3. The gene structures were verified and mutation detection was performed in 47 IBD patients. A total of 30 single nucleotide polymorphisms (SNPs) were tested for association to ulcerative colitis (UC, N = 317) and Crohn's disease (CD, N = 631) in a German cohort and verified in a UK cohort of 384 CD and 311 UC patients. An association signal was identified in the 5' region of the AGR2 gene (most significant SNP hcv1702494, nominal P(TDT) = 0.011, P(case/control) = 0.0007, OR = 1.34, combined cohort). The risk haplotype carried an odds ratio of 1.43 in the German population (P = 0.002). AGR2 was downregulated in UC patients as compared to normal controls (P < 0.001) and a trend toward lower expression was seen in carriers of the risk alleles. Luciferase assays of the AGR2 promoter showed regulation by the goblet cell-specific transcription factors FOXA1 and FOXA2. In summary, AGR2 represents an interesting new avenue into the etiopathophysiology of IBD and the maintenance of epithelial integrity.
Zheng
W
W
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
Rosenstiel
P
P
Huse
K
K
Sina
C
C
Valentonyte
R
R
Mah
N
N
Zeitlmann
L
L
Grosse
J
J
Ruf
N
N
Nürnberg
P
P
Costello
C M
CM
Onnie
C
C
Mathew
C
C
Platzer
M
M
Schreiber
S
S
Hampe
J
J
D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009088:Mucoproteins; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D015513:Oncogene Proteins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
C502296:AGR2 protein, human; C472588:AGR3 protein, human; D002352:Carrier Proteins; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009088:Mucoproteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011506:Proteins; D051542:Hepatocyte Nuclear Factor 3-beta