TY - JOUR
T1 - A major quantitative trait locus on chromosome 3 controls colitis severity in IL-10-deficient mice
AU - Farmer, Mark A.
AU - Sundberg, John P.
AU - Bristol, Ian J.
AU - Churchill, Gary A.
AU - Li, Renhua
AU - Elson, Charles O.
AU - Leiter, Edward H.
PY - 2001/11/20
Y1 - 2001/11/20
N2 - Colitic lesions are much more severe in C3H/HeJBir (C3H) than C57BL/6J (B6) mice after 10 backcrosses of a disrupted interleukin-10 (1110) gene. This study identified cytokine deficiency-induced colitis susceptibility (Cdcs) modifiers by using quantitative trait locus (QTL) analysis. A segregating F2 population (n = 408) of IL-10-deficient mice was genotyped and necropsied at 6 weeks of age. A major C3H-derived colitogenic QTL (Cdcs1) on chromosome (Chr.) 3 contributed to lesions in both cecum [logarithm of odds ratio (LOD) = 14.6)] and colon (LOD = 26.5) as well as colitis-related phenotypes such as spleen/body weight ratio, mesenteric lymph node/body weight ratio, and secretory IgA levels. Evidence for other C3H QTL on Chr. 1 (Cdcs2) and Chr. 2 (Cdcs3) was obtained. Cdcs1 interacted epistatically or contributed additively with loci on other chromosomes. The resistant B6 background also contributed colitogenic QTL: Cdcs4 (Chr. 8), Cdcs5 (Chr. 17, MHC), and Cdcs6 (Chr. 18). Epistatic interactions between B6 QTL on Chr. 8 and 18 contributing to cecum hyperplasia were particularly striking. In conclusion, a colitogenic susceptibility QTL on Chr. 3 has been shown to exacerbate colitis in combination with modifiers contributed from both parental genomes. The complex nature of interactions among loci in this mouse model system, coupled with separate deleterious contributions from both parental strains, illustrates why detection of human inflammatory bowel disease linkages has proven to be so difficult. A human ortholog of the Chr. 3 QTL, if one exists, would map to Chr. 4q or 1p.
AB - Colitic lesions are much more severe in C3H/HeJBir (C3H) than C57BL/6J (B6) mice after 10 backcrosses of a disrupted interleukin-10 (1110) gene. This study identified cytokine deficiency-induced colitis susceptibility (Cdcs) modifiers by using quantitative trait locus (QTL) analysis. A segregating F2 population (n = 408) of IL-10-deficient mice was genotyped and necropsied at 6 weeks of age. A major C3H-derived colitogenic QTL (Cdcs1) on chromosome (Chr.) 3 contributed to lesions in both cecum [logarithm of odds ratio (LOD) = 14.6)] and colon (LOD = 26.5) as well as colitis-related phenotypes such as spleen/body weight ratio, mesenteric lymph node/body weight ratio, and secretory IgA levels. Evidence for other C3H QTL on Chr. 1 (Cdcs2) and Chr. 2 (Cdcs3) was obtained. Cdcs1 interacted epistatically or contributed additively with loci on other chromosomes. The resistant B6 background also contributed colitogenic QTL: Cdcs4 (Chr. 8), Cdcs5 (Chr. 17, MHC), and Cdcs6 (Chr. 18). Epistatic interactions between B6 QTL on Chr. 8 and 18 contributing to cecum hyperplasia were particularly striking. In conclusion, a colitogenic susceptibility QTL on Chr. 3 has been shown to exacerbate colitis in combination with modifiers contributed from both parental genomes. The complex nature of interactions among loci in this mouse model system, coupled with separate deleterious contributions from both parental strains, illustrates why detection of human inflammatory bowel disease linkages has proven to be so difficult. A human ortholog of the Chr. 3 QTL, if one exists, would map to Chr. 4q or 1p.
UR - http://www.scopus.com/inward/record.url?scp=0035923603&partnerID=8YFLogxK
U2 - 10.1073/pnas.241258698
DO - 10.1073/pnas.241258698
M3 - Article
C2 - 11707574
AN - SCOPUS:0035923603
SN - 0027-8424
VL - 98
SP - 13820
EP - 13825
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -