Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2.
BACKGROUND
Genetic background has a profound effect on inflammatory bowel disease. The Gpx1 and Gpx2 double knockout (GPX1/2-DKO) mice on a mixed C57BL/6 (B6) and 129S1/SvimJ (129) background exhibit spontaneous ileocolitis. The DKO mice on a B6 background have mild ileocolitis. We characterized the 129 DKO mice to identify a genetic locus affecting disease severity.


METHODS
We backcrossed B6;129 DKO mice to 129 and analyzed for ileocolitis penetrance and severity at N5, N7, and N10. By correlating disease severity with single-nucleotide polymorphism (SNP) markers, we identified a colitis locus.


RESULTS
As early as 9 days of age, 129 DKO N5 and N10 mice showed disease signs and morbidity. The N10 DKO mice had the severest colitis with nearly complete penetrance and high morbidity compared with other generations or backgrounds. 129 DKO mice had elevated colonic KC and SAA3 expression, shorter colon length, and cecal E. coli overgrowth compared to B6 DKO mice. Analysis of the B6 loci in 129 N5, N7, and N10 cohorts pointed to a region of chromosome 2: 119 Mbp contributing to mild symptoms.


CONCLUSIONS
GPX1/2-DKO mice on 129 genetic background have the most aggressive colitis compared to B6;129 and B6 colonies. A B6 locus significantly contributing the resistance resides on chromosome 2: 119 Mbp. This region coincides with cytokine-deficiency-induced colitis susceptibility, Cdcs3, identified in the resistant B6 and sensitive C3H/HeJBir (C3Bir) with IL-10 deficiency. A three-way SNP analysis between 129, B6, and C3Bir locus points the major candidate genes to B2m, Dnajc17, Duox2, Pla2g4b, Pla2g4e, Pla2g4f and Slc30a4.
Esworthy
R Steven
RS
Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, California, USA.
Kim
Byung-Wook
BW
Larson
Garrett P
GP
Yip
M L Richard
ML
Smith
David D
DD
Li
Min
M
Chu
Fong-Fong
FF
D000818:Animals; D017209:Apoptosis; D033481:Chromosomes, Mammalian / Q000235:genetics; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D056426:Genetic Loci / Q000235:genetics; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics*; D007082:Ileum / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D018345:Mice, Knockout / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
D015850:Interleukin-6; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse