MAGI2 genetic variation and inflammatory bowel disease.
BACKGROUND
Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens.


METHODS
We genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls.


RESULTS
The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002).


CONCLUSIONS
These findings support the significance of the epithelial barrier in IBD pathogenesis.
McGovern
Dermot P B
DP
Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. mcgovernd@cshs.org
Taylor
Kent D
KD
Landers
Carol
C
Derkowski
Carrie
C
Dutridge
Deb
D
Dubinsky
Marla
M
Ippoliti
Andy
A
Vasiliauskas
Eric
E
Mei
Ling
L
Mengesha
Emebet
E
King
Lily
L
Pressman
Sheila
S
Targan
Stephan R
SR
Rotter
Jerome I
JI
D048868:Adaptor Proteins, Signal Transducing; D000907:Antibodies, Bacterial / Q000097:blood; D000908:Antibodies, Fungal / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D003424:Crohn Disease / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D051528:Guanylate Kinases; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018272:Porins / Q000276:immunology; D011506:Proteins / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000907:Antibodies, Bacterial; D000908:Antibodies, Fungal; D015415:Biomarkers; D002352:Carrier Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D018272:Porins; D011506:Proteins; D051528:Guanylate Kinases; C485777:MAGI2 protein, human