A major quantitative trait locus on mouse chromosome 3 is involved in disease susceptibility in different colitis models.
OBJECTIVE
Mice with a disrupted gene for the G-protein alpha inhibitory 2 chain ( Gnai2 -/- ) develop a spontaneous colitis resembling human inflammatory bowel disease. Disease expression differs markedly between inbred strains of mice, indicating genetic control of disease susceptibility. We performed a genome-wide screen to localize the chromosomal regions regulating disease expression.


METHODS
A total of 284 F2 mice derived from resistant C57BL/6J Gnai2 -/- mice and susceptible C3H/HeN Gnai2 -/- mice were analyzed in a genome-wide screen for colitis susceptibility and severity.


RESULTS
A highly significant locus on chromosome 3 (Gpdc1) contributed to colitis susceptibility and severity (likelihood ratio statistics [LRS] = 32.4; LOD score = 7; P < 1.0 x 10(-5)). The peak linkage of this locus at 62 cM colocalizes exactly with a previously identified locus controlling colitis susceptibility in interleukin-10-deficient mice. In addition, evidence for linkage with a locus on chromosome 1 (Gpdc2 ; LRS = 19.7; LOD = 4.3) was found, and the 2 loci interacted epistatically (combined LRS = 68.2). A third locus (Gpdc3) was found on chromosome 9 and this locus interacted epistatically with a locus on chromosome 7, which by itself did not have an effect on the trait.


CONCLUSIONS
The identification of a major locus on chromosome 3 that controls susceptibility to spontaneous colitis in 2 different gene-knockout models indicates that this locus harbors a gene(s) that plays a key role in maintaining mucosal homeostasis. Identification of this gene(s) may contribute to further understanding of the mechanisms underlying human inflammatory bowel disease.
Borm
Michelle E A
ME
Department of Immunogenetics, Vrije Universiteit Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
He
Jianping
J
Kelsall
Brian
B
Peña
A Salvador
AS
Strober
Warren
W
Bouma
Gerd
G
D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003092:Colitis / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D005838:Genotype; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse