Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Abeta42 in 24 extended LOAD families and for association with LOAD in two independent case-control series. One series (MCR, 188 age-matched case-control pairs) did not show association (p=0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age-matched case-control pairs) showed significant (p=0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR]=5.1, p=0.003) and H2(H7) haplotypes (OR=0.60, p=0.04) had the same effects previously reported. In this series, the H8 haplotype (OR=2.7, p=0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Abeta42 (p=0.02). In addition, the H5(H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Abeta42 (p=0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD.
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PMID:Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. 1502 28

Genetic and biological studies point to a role for insulin-degrading enzyme (IDE) in Alzheimer's disease (AD). Two SNP-based studies recently reported evidence for association with AD using markers in a approximately 270 kb haplotype block on chromosome 10q. This haplotype block region harbors three known genes; insulin-degrading enzyme (IDE), kinesin family member 11 (KIF11), and hematopoietically expressed homeobox (HHEX). In an attempt to search for susceptibility variants we have sequenced all coding exons, 2 kb of 5' and 3'-flanking sequence, and all regions showing a high degree of human-mouse conservation in these three genes in 30 individuals. We found a total of 40 single nucleotide polymorphisms and 8 insertion/deletion polymorphisms. No coding variants were identified in any of the three genes. Nine polymorphisms in IDE and four polymorphisms in KIF11 situated in conserved regions or near coding exons were subsequently genotyped in a set of AD cases and controls. Two markers in KIF11 yielded borderline significant results in the ApoE4 non-carrier subgroup, but the results were otherwise not significant in this small set of samples. This study of multiple new markers in the region will facilitate further association studies in this important AD region.
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PMID:Mutation screening of a haplotype block around the insulin degrading enzyme gene and association with Alzheimer's disease. 1585 21