A major quantitative trait locus on chromosome 3 controls colitis severityin IL-10-deficient mice

Colitic lesions are much more severe in C3H/HeJBir (C3H) than C57BL/6J (B6) mice after 10 backcrosses of a disrupted interleukin-10 (1/10) gene. This study identified cytokine deficiency-induced colitis susceptibility (Cdcs) modifiers by using quantitative trait locus (QTL) analysis. A segregating F -2 population (n = 408) of IL-10-deficient mice was genotyped and necropsie d at 6 weeks of age. A major C3H-derived colitogenic QTL (Cdcs1) on chromos ome (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 als o contributed colitogenic QTL: Cdcs4 (Chr. 8), Cdcs5 (Chr. 17, MHC) and Cdc s6 (Chr. 18). Epistatic interactions between B6 QTL on Chr. 8 and 18 contri buting to cecum hyperplasia were particularly striking. In conclusion, a co litogenic 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, coupl ed with separate deleterious contributions from both parental strains, illu strates why detection of human inflammatory bowel disease linkages has prov en to be so difficult. A human ortholog of the Chr. 3 QTL, if one exists, w ould map to Chr. 4q or 1p.