The interferon-gamma gene as a positional and functional candidate gene for inflammatory bowel disease

Epidemiological and genome-wide linkage analyses have provided firm evidenc e for a genetic component in the pathogenesis of inflammatory bowel disease . The linkage regions on chromosomes 12 and 16 have been replicated in seve ral-independent samples. These represent the best positional evidence in th e search for inflammatory bower disease susceptibility genes. While systema tic association and physical mapping studies in these regions are under way , the direct analysis of immunologically relevant genes as positional and f unctional candidates may provide a shortcut in this process. The interferon -gamma gene resides in the chromosome 12 linkage region near the marker D12 S83. Interferon-gamma is an important proinflammatory cytokine in the inter leukin-12 cascade and has been implicated in the pathogenesis of mucosal in flammation. We tested this gene for evidence of linkage and association in 133 German multiplex families and 506 single patients with their parents. A n intragenic, highly informative CA-repeat marker in intron 1 of the gene w as typed using fluorescence-labeled polymerase chain reaction and analysis on an automated sequencer. In the nonparametric linkage analysis using GENE HUNTER, a nonsignificant maximum LOD score of 0.67 was obtained. The transm ission disequilibrium test for association was negative (P greater than or equal to 0.22) for Crohn's disease, ulcerative colitis, and the combined in flammatory bowel disease phenotype. In summary, the findings make interfero n-gamma a very unlikely candidate for the major susceptibility gene in the chromosome 12 linkage interval. Future efforts can concentrate on other tra nscripts in the region.