Abstracts

We previously reported strong evidence of linkage of IGE to chromosome 18 (lod = 5.2) [Durner et al 2001]. Our goal here is identifying the IGE-related locus indicated by the linkage result. We typed 35 SNPs on chr.18 near D18S474 in 147 IGE patients + 126 controls. 96 families were used in family-based association tests (TDT). SNPs centromeric to D18S474 showed highly significant association with case control (fig. 1) and TDT (fig. 2) analyses (p[lt].0001). The strongest association was in the region of Malic Enzyme (ME2). The original linkage analysis supported recessive inheritance, so we tested IGE association with homozygotes vs. heterozygotes to test the mode of inheritance. SNP homozygotes were associated with the disease compared to heterozygotes. These association and linkage findings are in accord with the observation that enzyme-related diseases tend to show recessive inheritance. Also, at the 5[apos] end of ME2, there is a block (100-200 kb) of strong marker-marker disequilibrium.[figure1][figure2] This report represents the second suggested IGE locus based on analysis of families collected specifically for common forms of IGE, and in a genomic region previously identified through linkage analysis. The association evidence suggests that ME2, or a close neighbor, is a major susceptibility locus for IGE and especially JME. There are no known channel genes in this region. ME2 is a genome-coded enzyme which localizes in the mitochondria. Thus, if ME2 is the susceptibility locus, then one might infer that variations in energy metabolism of the cell or pathways of apoptosis during brain development may be critical in susceptibility to common IGE. This notion supports etiologic mechanisms related to development previously suggested by the finding that BRD2, a nuclear transcription factor, is involved in the expression of forms of JME. (Supported by NS27941, DK31775, MH48858, and NS37466 from NIH)