Genetic variation in a haplotype block spanningIDE influences Alzheimer disease

Abstract

Communicated by Richard G. H. CottonLinkage studies have identified a large (460-Mb) region on chromosome 10q that segregates with Alzheimer Disease (AD). Within the region, the gene for insulin degrading enzyme (IDE) represents a notable biological candidate given that it degrades amyloid b-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by c-secretase processing. We have used a single nucleotide polymorphism (SNP) genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. A 276-kb linkage disequilibrium block was revealed that spans three genes (IDE, KNSL1, and HHEX). Assessing this block in several independent sets of case-control materials (early-and late-onset AD) and focusing also upon quantitative measures that are pertinent to AD diagnosis and severity (MMSE scores, microtubule-associated protein Tau [MAPT] levels in CSF, degree of brain pathology, and age-at-onset) produced extensive evidence for significant AD association. Signals (p-values ranging from 0.05 to o1 Â 10 À9 ) were generally stronger when examining haplotypes rather than individual SNPs, and quantitative trait tests most uniformly revealed the detected associations. Consistent risk alleles and haplotypes were apparent across the study, with effects in some cases as large as that of the e4 allele of APOE. A subsequent mutation screen of exons in all three suspect genes provided no evidence for common causative mutations. These results provide substantial evidence that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD.

Quantitative Trait Loci Near the Insulin-Degrading Enzyme (IDE) Gene Contribute to Variation in Plasma Insulin Levels

“…All 14 markers were found to be in Hardy-Weinberg equilibrium. Pairwise marker correlations suggested strong LD in the region, in agreement with earlier data (13). Common haplotypes (those Ͼ5% frequency), inferred with HAPLOTYPER using all 14 markers, were similar to those obtained based on a slightly modified marker set (13).…”

“…Numerous studies have detected genetic effects exclusively in men (20,21), and sex specificity may be a major confounding factor in genetic analyses (22). Third, the marker that was in strongest association with quantitative traits related to Alzheimer's disease in our recent study (13) was rs2251101 (from among 26 markers). Importantly, however, the present analyses suggest that there may be more than one functionally relevant polymorphic site in or near IDE.…”

“…Assays in which all 32 samples were monomorphic were excluded from further analysis. For convenience, the nomenclature used throughout this report to refer to SNPs is the same as that used in our recent report (13). Genotyping.…”

“…This study follows a recent report (13) in which we examined 26 polymorphic markers extending across IDE in relation to Alzheimer's disease in a large Swedish population. These were used to define regional linkage disequilibrium (LD) structure, which highlighted a LD block spanning 276 kb around IDE.…”

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

“…19,20 Several genetic association studies tested for an association between neprilysin or insulysin gene variants and AD, but gave controversial results. [21][22][23][24][25] To date, the expression of ECE-1 in human brain had never been studied, and its potential role in the pathogenesis of AD had never been assessed. We have addressed this question by a combination of expression and genetic studies, and provide evidence for a protective role of ECE-1 against AD in the aging brain.…”