Identification of the Gasa3 and Gasa4 autoimmune gastritis susceptibility genes using congenic mice and partitioned, segregative and interaction analyses

BALB/c mice thymectomized on their third day of life develop a high incidence of experimental autoimmune gastritis (EAG) which closely resembles human chronic atrophic (type A, autoimmune) gastritis. Linkage analysis of (BALB/cCrSlc×C57BL/6)F2 mice previously demonstrated that the Gasa1 and Gasa2 genes on distal Chromosome (Chr) 4 have major effects on the development of EAG in this murine model, while other loci displayed a trend towards linkage. Here, we implemented partitioned χ2-analysis in order to develop a better understanding of the genotypes contributing to susceptibility and resistance at each linkage region. This approach revealed that linkage of Gasa1 and Gasa2 to EAG was due to codominant and recessive BALB/cCrSlc alleles, respectively. To identify additional EAG susceptibility genes, separate linkage studies were performed on Gasa1 heterozygotes and Gasa2 C57BL/6 homozygotes plus heterozygotes so as to minimize the effects of these disease genes. The enhanced sensitivity of these analyses confirmed the existence of a third EAG susceptibility gene (designated Gasa3) on Chr 6. Epistatic interactions between the Gasa2 EAG susceptibility gene and the H2 were also identified, and the presence of an H2-linked susceptibility gene (Gasa4) confirmed by analysis of H2 congenic mice