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• W2135842091 abstract "Background & Aims: Mice with a disrupted gene for the G-protein α 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 × 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. Background & Aims: Mice with a disrupted gene for the G-protein α 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 × 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. While the exact cause of the 2 major forms of inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis, is still unclear, there is a growing agreement that they occur as the consequence of a genetically determined dysregulated immune response to one or more antigens from the mucosal microflora.1Bouma G. Strober W. The immunological and genetic basis of inflammatory bowel disease.Nat Rev Immunol. 2003; 3: 521-533Crossref PubMed Scopus (1497) Google Scholar The fact that this abnormality has strong genetic underpinnings has long been recognized, and in recent years a number of IBD susceptibility loci have been established by linkage studies.2Bonen D.K. Cho J.H. The genetics of inflammatory bowel disease.Gastroenterology. 2003; 124: 521-536Abstract Full Text PDF PubMed Scopus (399) Google Scholar Moreover, the susceptibility conferred by one of these loci (IBD1) has been shown to be due to mutations in the NOD2 (CARD15) gene; when present on both chromosomes, this causes CD in 8%–17% of white patients with CD.3Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O’Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4691) Google Scholar, 4Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nunez G. Cho J.H. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (4174) Google Scholar It is now known that NOD2 is an intracellular sensor of a component of bacterial peptidoglycan (muramyl dipeptide) that regulates nuclear factor κB activation5Inohara N. Ogura Y. Fontalba A. Gutierrez O. Pons F. Crespo J. Fukase K. Inamura S. Kusumoto S. Hashimoto M. Foster S.J. Moran A.P. Fernandez-Luna J.L. Nunez G. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease.J Biol Chem. 2003; 278: 5509-5512Crossref PubMed Scopus (1405) Google Scholar; nevertheless, it is not yet known how this abnormality leads to CD and/or a dysregulated immune response. In addition, the fact that NOD2 mutations occur in only a minority of patients with CD underscores the fact that it accounts for only a small part of the genetic factors underlying CD as a whole and suggests that the mucosal immune deregulation causing this disease can have many causes. An important step forward in the understanding of IBD has come from the identification of animal models of mucosal inflammation that more or less resemble human IBD.6Strober W. Fuss I.J. Blumberg R.S. The immunology of mucosal models of inflammation.Annu Rev Immunol. 2002; 20: 495-549Crossref PubMed Scopus (1147) Google Scholar One of the key findings to emerge from the study of these models is that susceptibility to colitis in most, if not all, of the experimental models is influenced by the strain of the mouse in which the model is expressed. These strain differences in disease susceptibility offer the opportunity to identify genes that are involved in determining susceptibility/resistance to mucosal inflammation and, as such, may contribute to the identification of the genes involved in human IBD. One mouse model that displays such strain differences in susceptibility is the spontaneous colitis model occurring in mice deficient in the G-protein α inhibitory 2 chain (Gnai2).7Lombardi M.S. Kavelaars A. Heijnen C.J. Role and modulation of G protein-coupled receptor signaling in inflammatory processes.Crit Rev Immunol. 2002; 22: 141-163Crossref PubMed Google Scholar, 8Radhika V. Dhanasekaran N. Transforming G proteins.Oncogene. 2001; 20: 1607-1614Crossref PubMed Scopus (123) Google Scholar, 9Braun M.C. Kelsall B.L. Regulation of interleukin-12 production by G-protein-coupled receptors.Microbes Infect. 2001; 3: 99-107Crossref PubMed Scopus (63) Google Scholar, 10Rudolph U. Finegold M.J. Rich S.S. Harriman G.R. Srinivasan Y. Brabet P. Boulay G. Bradley A. Birnbaumer L. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice.Nat Genet. 1995; 10: 143-150Crossref PubMed Scopus (363) Google Scholar Such mice most likely develop mucosal inflammation because signaling through Gnai2 normally inhibits interleukin (IL)-12 production and thus, in the absence of this molecule, IL-12 production and the Th1 response is greatly exaggerated. The strain-specific variation in inflammation observed in this model is exemplified by the fact that the C3H/HeN strain is highly susceptible to disease, whereas the C57BL/6J strain maintained under identical circumstances is highly resistant. As implied above, this introduces the possibility that a genetic analysis of these strains of Gnai2−/− mice might lead to the identification of modifying genes critical to the expression of colitis in these mice. On this basis, we performed such a genetic analysis of Gnai2−/− mice using genome-wide microsatellite methodology to identify genetic susceptibility loci in Gnai2−/− (C3H/HeNxC57BL/6J) F2 generation intercrosses. This genetic screening procedure allowed identification of a highly significant susceptibility locus on chromosome 3 as well as additional loci on chromosome 1, chromosome 9, and the X chromosome. The importance of the chromosome 3 locus is emphasized by the fact that this locus also is likely to be involved in the strain variation in disease susceptibility found in IL-10 knockout mice.11Farmer M.A. Sundberg J.P. Bristol I.J. Churchill G.A. Li R. Elson C.O. Leiter E.H. A major quantitative trait locus on chromosome 3 controls colitis severity in IL-10-deficient mice.Proc Natl Acad Sci U S A. 2001; 98: 13820-13825Crossref PubMed Scopus (104) Google Scholar Specific pathogen-free, 5–6-week-old C3H/HeN mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Gnai2 knockout mice on the C57BL/6J background were bred from homozygous C57BL/6J breeding pairs as described before10Rudolph U. Finegold M.J. Rich S.S. Harriman G.R. Srinivasan Y. Brabet P. Boulay G. Bradley A. Birnbaumer L. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice.Nat Genet. 1995; 10: 143-150Crossref PubMed Scopus (363) Google Scholar, 12He J. Gurunathan S. Iwasaki A. Ash-Shaheed B. Kelsall B.L. Primary role for Gi protein signaling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses.J Exp Med. 2000; 191: 1605-1610Crossref PubMed Scopus (91) Google Scholar and were originally generated at Baylor University School of Medicine. The Gnai2 deficiency was backcrossed from the C57BL/6J background onto the C3H/HeN strain for >6 generations. Because Gnai2 deficiency causes severe inflammation in C3H/HeN mice, resulting in early death and loss of desire to breed, these mice were maintained in the heterozygous state (Gnai2+/−). C57BL/6J × C3H/HeN Gnai2−/− F1 hybrids were derived from the reciprocal mating of C57BL/6J Gnai2−/− mice with C3H/HeN Gnai2+/− mice and subsequent genotypic selection for the Gnai2−/− deficiency. These mice were used to generate a first group of 147 F2 mice by brother-sister mating of F1 Gnai2−/− mice, and this group of mice was analyzed using a genome-wide screen. Meanwhile, an additional group of 137 F2 mice was generated, for a total of 284 F2 mice (146 female and 138 male). Mice were maintained in the animal holding facilities of the National Institute of Allergy and Infectious Diseases, and all breeding pairs were set up randomly. Animal use adhered to National Institutes of Health Laboratory Animal Care Guidelines. Susceptibility to and severity of colitis in F2 mice were determined by weekly monitoring of clinical signs of colitis, diarrhea, and weight loss. Mice were killed when they showed profound weight loss and/or signs of colitis. Mice that showed no signs of disease and no weight loss at the age of 5 months were considered resistant to colitis and were killed as well. Blood was drawn from all mice for serologic studies, and colons were removed for histopathologic analysis. Colonic tissue specimens were obtained from all killed mice and fixed in 10% buffered formalin phosphate (Sigma-Aldrich, Zwijndrecht, The Netherlands). The specimens were embedded in paraffin, cut into sections, and stained with H&E. The degree of inflammation on microscopic horizontal sections of the entire colon was graded semiquantitatively from 0 to 4 as described previously13Neurath M.F. Fuss I. Kelsall B.L. Presky D.H. Waegell W. Strober W. Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance.J Exp Med. 1996; 183: 2605-2616Crossref PubMed Scopus (383) Google Scholar (in short: 0, no evidence of inflammation; 1, low level of lymphocyte infiltration with infiltration seen in 10% high-power fields and no structural changes observed; 2, moderate lymphocyte infiltration with infiltration seen in 10%–25% high-power fields, crypt elongation, bowel wall thickening that does not extend beyond the mucosal layer, and no evidence of ulceration; 3, high level of lymphocyte infiltration with infiltration seen in 25%–50% high-power fields, high vascular density, and thickening of the bowel wall that extends beyond the mucosal layer; 4, marked degree of lymphocyte infiltration with infiltration seen in 50% high-power fields, high vascular density, crypt elongation with distortion, and transmural bowel wall thickening with ulceration). To define a semiquantitative and gradual division of the disease expression in F2 mice, we created a total score of disease severity, combining the percentage of weight loss, the age at the time the mice were killed, and the histologic score by assigning a score from 0 to 4 for each grade of the corresponding trait (Table 1). If mice were found dead (due to rapid disease progression), an extra point was added to the total score. Theoretically, this would result in a maximum score of 13. Animals were considered resistant when they had a total disease score of 3 or less, implicating they displayed no or only minimal clinical or histologic signs of disease when killed at age 20 weeks or older, whereas mice with a total score of 4 or higher were considered susceptible. We had previously established that mice that had not developed any signs of disease by the age of 20 weeks would not do so if they were followed up for a longer period (up to 1 year; data not shown). Therefore, mice that did not develop any signs of disease were killed at the age of 20 weeks.Table 1Definition of Disease Severity in Gnai2-Deficient F2 MiceScoreHistology% Weight lossAge at death (wk)000–426+115–920–252210–1915–193320–2910–144430+0–9NOTE. Total score of colitis was determined by the sum of the score for each trait (histology, weight loss, age at death) and adding an extra point if an animal was found dead. Open table in a new tab NOTE. Total score of colitis was determined by the sum of the score for each trait (histology, weight loss, age at death) and adding an extra point if an animal was found dead. In part of the analysis, the phenotypic extremes were analyzed. These included on the one hand most resistant mice with a disease score of 0–2 and on the other hand most susceptible mice with a score of 8 or higher. Spleens were taken from all mice and frozen at −70°C. DNA was isolated using a commercial kit as described by the manufacturer (Biozym; Gentra Systems, Landgraaf, The Netherlands). Primers for microsatellite markers that differ at least 6 base pairs in size between susceptible C3H/HeN mice and resistant C57BL/6J mice were selected from online available databases (CIDR; http://www.cidr.jhmi.edu/mouse/mouse.html) and The Jackson Laboratory (http://www.informatics.jax.org/) and purchased from Invitrogen Life Technologies (Breda, The Netherlands). A total of 134 microsatellite markers equally dispersed along the mouse autosomes and the X chromosome were selected for genotypic analysis. Using these markers, a genetic map was generated with an average locus distance of 12 cM, with the largest distance (28 cM) on proximal chromosome 2 between markers D2Mit1 and D2Mit242. The markers used in this study will be published online (http://www.immunogenetics.nl). To evaluate which markers cosegregate with disease phenotype, a first group of 147 mice was selected for a genome-wide screen: 56 resistant F2 mice (30 female and 26 male) with a disease score of 3 or less and 91 F2 susceptible mice (47 female and 44 male) with a disease score of 4 or higher. From this group, 76 mice were selected with the most distinct phenotypes (47 resistant and 29 with severe colitis). Genetic regions that showed suggestive or significant linkage, either from the group with the extreme phenotypes or the total first group, were then further investigated by genotyping the remainder of the eligible mice. Polymerase chain reaction (PCR) amplification was performed in GeneAmp PCR System 9600 and GeneAmp PCR System 9700 (both PE Applied Biosystems, Niewerkerk aan den IJssel, The Netherlands) in 96-well plates in 10-μL volumes using a protocol provided by the manufacturer (Research Genetics, Invitrogen). Thirty cycles at 94°C for 45 seconds, 55°C for 45 seconds, and 72°C for 60 seconds followed by an extension period at 72°C for 7 minutes was generally used, although some primers required a slightly different annealing temperature for optimum amplification. After PCR amplification, PCR products were run on 4% agarose gels (in a mixture of 2% ultrapure agarose [NuSieve GTG Agarose; Cambrex Bio Science Rockland, Rockland, ME]) and 2% low melting agarose (Invitrogen) and visualized by ethidium bromide (Invitrogen) staining. The MapManager software package was used to construct linkage maps with microsatellite markers that experimentally showed polymorphism between the C3H/HeN and the C57BL/6J strain (http://mapmgr.roswellpark.org/mmQTX.html). Likelihood ratio statistics (LRS) values for colitis severity were calculated with MapManager QTXb18 version 0.27 in populations of females and males, females alone, and males alone. Logarithm of the odds (LOD) scores were determined by LRS/2ln10. Empiric thresholds for suggestive and significant linkage were determined by permutation analysis using the MapManager software package with 1000 permutations. Gene-gene interactions between the different genetic loci were identified using the same statistical program. For nonparametric linkage analysis of resistant and susceptible mice, χ2 analysis was performed using GraphPad InStat version 3.05 for Windows 95 (GraphPad Software, San Diego, CA; http://www.graphpad.com). A χ2 test statistic for each marker locus was derived using 2 × 3 contingency tables to test for linkage. We generated homozygous C3H/HeN Gnai2-deficient mice by crossing C57BL/6J Gnai2-deficient mice with C3H/HeN mice, backcrossing F1 mice carrying the gene defect to C3H/HeN mice for >6 generations, and then intercrossing to obtain homozygous mice. Such homozygous Gnai2-deficient (Gnai2−/−) C3H/HeN mice, when reared under specific pathogen-free conditions, were highly susceptible to colitis (Figure 1). As previously described, colitis in C3H/HeN Gnai2−/− mice is characterized by severe diarrhea and weight loss, frequently accompanied by rectal prolapse and dilation of the colon.10Rudolph U. Finegold M.J. Rich S.S. Harriman G.R. Srinivasan Y. Brabet P. Boulay G. Bradley A. Birnbaumer L. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice.Nat Genet. 1995; 10: 143-150Crossref PubMed Scopus (363) Google Scholar In general, only the distal half of the colon is involved, with a sharp demarcation between the involved and noninvolved areas. Microscopically, massive infiltrations of lymphocytic cells are seen, accompanied by depletion of goblet cells, crypt elongation, high vascular density, and transmural bowel wall thickening with ulceration (Figure 2).Figure 2Microscopic views of normal and diseased colons. Representative H&E-stained longitudinal sections of colons of (A) wild-type C3H/HeN, (B) Gnai2−/− C3H/HeN, (C) wild-type C57BL/6J, (D) Gnai2−/− C57BL/6J, (E) Gnai2−/− C3H/HeN × C57BL/6J F1, and (F–J) Gnai2−/− F2 mice, with increasing histologic scores. (Original magnification 100×.)View Large Image Figure ViewerDownload (PPT) C3H/HeN Gnai2−/− mice display a greatly reduced survival rate and in general breed poorly, probably because most mice develop disease before the reproductive age. Colitis develops in these mice as early as week 6 and, even before full onset of gastrointestinal disease, the animals exhibit decreased body weight as compared with their wild-type littermates (data not shown). Therefore, for breeding purposes, the C3H/HeN mice were maintained in a heterozygous state for the Gnai2 deficiency (Gnai2+/−). Based on genotyping the offspring of Gnai2+/− × Gnai2+/− mice, the frequency of homozygous Gnai2-deficient mice was markedly below the expected 25%, indicating intrauterine death in a significant number of Gnai2−/− mice (results not shown). Interestingly, heterozygous Gnai2 C3H/HeN-deficient mice did not develop any signs of disease, indicating that colitis only occurs if no functional Gnai2 is present (Figure 1). Whereas C3H/HeN Gnai2−/− mice are highly susceptible to colitis, C57BL/6J Gnai2−/− mice are highly resistant and disease did not occur in these mice even when the latter were followed up for as long as 6 months (Figure 1); in addition, upon necropsy, colons of these mice were normal, both macroscopically and microscopically (Figure 2C and D). The F1 generation was generated by crossing C3H/HeN Gnai2+/− mice with C57BL/6J Gnai2−/− mice. As expected, 50% of the offspring were homozygous for the Gnai2 deficiency, and these mice were used for further analysis and breeding purposes. The Gnai2−/− F1 offspring were relatively resistant to colitis. Thus, in general, these animals did not develop weight loss, diarrhea, or macroscopic signs of colitis, although occasionally some histologic abnormalities were found (Figure 2E). A total of 284 F2 mice (138 male and 146 female) were generated by interbreeding the Gnai2−/− F1 generation. As can be seen from Figure 2, Figure 3, the F2 population displayed a broad spectrum of disease, varying from highly resistant with no clinical and histologic signs of illness to highly susceptible with severe colitis. The severity of colitis was determined using a semiquantitative classification as described in detail in Materials and Methods. However, as can also be seen from Figure 3, the trait followed an essentially bimodal distribution. Thus, in part of the analysis, the trait was analyzed as a qualitative trait: mice with a disease score of 3 or less (n = 145; 79 male and 66 female) were considered resistant to colitis because they did not exhibit any clinical signs of disease and, in addition, displayed no or only minimal weight loss and histologic abnormalities (Table 1). In contrast, a total of 139 mice (59 male and 80 female) displayed clinical signs of disease accompanied by significant weight loss and histologic disease (ie, a disease score of 4 or higher) and were considered susceptible. Overall, female mice were somewhat more susceptible to colitis than male mice. This was reflected in the mean colitis score, which was higher in female mice than in male mice (4.9 vs 4.2; P < .05). Occasionally, histologic signs indicative of colon carcinoma were found in F2 mice. This occurred exclusively in mice with severe inflammation. However, there was no clear correlation between occurrence of carcinoma and the duration of the disease, because, in some instances, neoplastic lesions were found in mice as young as 9 weeks. To identify the genetic regions determining the differences in susceptibility between susceptible C3H/HeN and resistant C57BL/6J mice, we genotyped the initial group of 147 F2 mice of our cohort with a panel of 134 microsatellite markers equally dispersed among the genome. We first analyzed disease in the F2 population as a qualitative (binary) trait (ie, susceptible vs resistant mice). Among the 147 mice, 56 (30 female and 26 male) were relatively resistant, with a disease score of 3 or less, whereas 91 (47 female and 44 male) were susceptible (with a disease score of 4 or higher). Contrasting genotype and allele frequencies of these groups led to the identification of 4 chromosomal regions that exhibited an association suggestive for linkage (P < 1.6 × 10−3 or stronger).14Lander E. Kruglyak L. Genetic dissection of complex traits guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4472) Google Scholar These loci reside on chromosomes 1, 3, and 13 and the X chromosome. Subsequently, the subgroup of mice with the most extreme phenotypes was analyzed. This analysis has the advantage that the phenotypes of these groups are clearly distinct and nonoverlapping and the disadvantage of lower statistical power due to the lower sample number. Contrasting mice with a disease score of 2 or less with those with a disease score of 8 or higher resulted in essentially the same associations. In addition, this analysis allowed identification of an association with a locus on chromosome 9, which was not found in the entire group of mice. Finally, disease was considered as a quantitative trait in which the genes contribute to the trait in a continuous fashion rather than in a discrete way. This was accomplished by a total disease score, which takes into account histologic score, weight loss, and the age at which the mice were killed (Table 1). Due to the semiquantitative nature of our phenotypes, we established an empiric genome-wide significance level for our data set by performing a permutation analysis. The observed genotypes of the F2 animals were kept constant while the phenotypes were randomly shuffled over the genotype data, thereby efficiently disrupting any genotype-phenotype correlation. Linkage analysis was performed, and the strongest association (expressed as the LRS) in each experiment was recorded. This procedure was repeated 1000 times, and through this method the LRS threshold for 95% significance was calculated to be 16.5. Suggestive linkage was calculated to be above a threshold LRS value of 10.0. All chromosomes with regions identified with the above strategies that showed at least suggestive linkage were genotyped in the entire cohort of 284 F2 mice to confirm or discard the linkage. Analysis of the entire F2 population of 284 mice as a qualitative trait confirmed the presence of a region on the distal part of chromosome 3 that is strongly associated with susceptibility to colitis. As can be seen from Table 2, the strongest association was found with microsatellite markers D3Mit316 at 59 cM (χ2 = 29.7; P < 1.0 × 10−5) and D3Mit348 at 61 cM (χ2 = 29.6; P < 1.0 × 10−5). Analysis of phenotypic extremes led to a similarly significant association with these markers (χ2 = 32; P < 1.0 × 10−5, data not shown). When mice were subdivided according to sex, the same significant associations were found in both males and females.Table 2Distribution of Genotypes Surrounding the Locus on Chromosome 3 Regulating Susceptibility to Colitis in Gnai2-Deficient F2 MiceMarkerPosition (cM)GenotypeResistant (n)Susceptible (n)Pχ2D3Mit30722BB44322.5 × 10−311.9BC6077CC2150D3Mit13735BB41341.0 × 10−418.1BC6565CC1960D3Mit31038BB4034<1.0 × 10−521.7BC6864CC1761D3Mit18949BB4330<1.0 × 10−524.3BC6567CC1762D3Mit7855BB4232<1.0 × 10−524.8BC6765CC1662D3Mit31659BB3933<1.0 × 10−529.7BC7262CC1464D3Mit34861.2BB4237<1.0 × 10−529.6BC6958CC1464D3Mit14779.4BB39385.0 × 10−415.2BC6864CC1857D3Mit1987.6BB3937.028.0BC6471CC2251NOTE. Microsatellite analysis of chromosome 3. Numbers of different genotypes were compared between susceptible and resistant mice in a contingency table using the χ2 test for independence. Markers at peak association are indicated in bold. BB, homozygous for the C57BL/6J strain; BC, heterozygous; CC, homozygous for the C3H/HeN strain. Open table in a new tab NOTE. Microsatellite analysis of chromosome 3. Numbers of different genotypes were compared between susceptible and resistant mice in a contingency table using the χ2 test for independence. Markers at peak association are indicated in bold. BB, homozygous for the C57BL/6J strain; BC, heterozygous; CC, homozygous for the C3H/HeN strain. We then analyzed the F2 population as a quantitative trait. As shown in Figure 4, this analysis confirmed the highly significant association with this region. The strongest association was again with the chromosomal region surrounding D3Mit348 at 61 cM. A peak LRS of 32.4, corresponding to a LOD score of 7, was found for this locus. The strength of the association markedly exceeded the threshold for significant linkage (LRS = 16.5) that was determined empirically by permutation analysis. We have provisionally designated this quantitative trait locus (QTL) Gpdc1, for G-protein deficiency-induced colitis. To study the mode of inheritance of this locus, we stratified mice according to their genotype at position D3Mit348 and determined the severity of colitis in these groups. As can be seen in Figure 5, F2 mice that were homozygous for the C75BL/6 allele at this position had a mean (±SEM) colitis score of 4.01 (±.31) and this was not significantly different from mice heterozygous for the C57BL/6J allele at this position, which had a mean score of 4.16 (±.27). This was in sharp contrast with the colitis score in mice homozygous for the C3H/HeN allele at this position (6.40 ± .32; P < .001). These findings are consistent with the view that 2 copies of the C3H allele at this position are required to develop colitis and help to explain the resistance in the F1 population of mice. Because the association with the region on chromosome 3 was remarkably strong, this locus might theoretically overshadow associations with other genetic loci that otherwise might have an important effect on the trait. We therefore performed sequential regression analyses in which we stratified for marker D3Mit348. This analysis continued to show" @default.
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• W2135842091 date "2005-01-01" @default.
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• W2135842091 title "A major quantitative trait locus on mouse chromosome 3 is involved in disease susceptibility in different colitis models" @default.
• W2135842091 cites W1642457845 @default.
• W2135842091 cites W1670573097 @default.
• W2135842091 cites W1935225932 @default.
• W2135842091 cites W1965614926 @default.
• W2135842091 cites W1967561218 @default.
• W2135842091 cites W1976741643 @default.
• W2135842091 cites W1979266771 @default.
• W2135842091 cites W1983715014 @default.
• W2135842091 cites W1984720175 @default.
• W2135842091 cites W1985260340 @default.
• W2135842091 cites W1991871348 @default.
• W2135842091 cites W2012528572 @default.
• W2135842091 cites W2017443683 @default.
• W2135842091 cites W2037673353 @default.
• W2135842091 cites W2065243538 @default.
• W2135842091 cites W2078730804 @default.
• W2135842091 cites W2088451184 @default.
• W2135842091 cites W2099376515 @default.
• W2135842091 cites W2106255211 @default.
• W2135842091 cites W2111900042 @default.
• W2135842091 cites W2129319296 @default.
• W2135842091 cites W2139625099 @default.
• W2135842091 cites W2147787161 @default.
• W2135842091 cites W2156456343 @default.
• W2135842091 cites W2165885428 @default.
• W2135842091 cites W2329936852 @default.
• W2135842091 cites W4229850346 @default.
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