Genetic Variants in a Haplotype Block Spanning IDE are Significantly Associated with Plasma Aβ42 Levels and Risk for Alzheimer Disease

Nilufer Taner, Mariet Allen, Daniel Fadale, Leah Scanlin, Linda Younkin, Ronald Carl Petersen, Neill R Graff Radford, Steven G Younkin

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Aβ42; 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 Aβ42 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 Aβ42 (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 Aβ42 (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.

Original languageEnglish (US)
Pages (from-to)334-342
Number of pages9
JournalHuman Mutation
Volume23
Issue number4
DOIs
StatePublished - 2004

Fingerprint

Haplotypes
Alzheimer Disease
Odds Ratio
Phenotype
Chromosomes
Amyloid
Genes

Keywords

  • AD
  • Alzheimer Disease
  • Amyloid beta
  • APP
  • IDE
  • Insulin-degrading enzyme
  • LOAD

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genetic Variants in a Haplotype Block Spanning IDE are Significantly Associated with Plasma Aβ42 Levels and Risk for Alzheimer Disease. / Taner, Nilufer; Allen, Mariet; Fadale, Daniel; Scanlin, Leah; Younkin, Linda; Petersen, Ronald Carl; Graff Radford, Neill R; Younkin, Steven G.

In: Human Mutation, Vol. 23, No. 4, 2004, p. 334-342.

Research output: Contribution to journalArticle

@article{0e08a5502ac5423eab60e578e317caf3,
title = "Genetic Variants in a Haplotype Block Spanning IDE are Significantly Associated with Plasma Aβ42 Levels and Risk for Alzheimer Disease",
abstract = "Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Aβ42; 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 Aβ42 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 Aβ42 (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 Aβ42 (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.",
keywords = "AD, Alzheimer Disease, Amyloid beta, APP, IDE, Insulin-degrading enzyme, LOAD",
author = "Nilufer Taner and Mariet Allen and Daniel Fadale and Leah Scanlin and Linda Younkin and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Younkin, {Steven G}",
year = "2004",
doi = "10.1002/humu.20016",
language = "English (US)",
volume = "23",
pages = "334--342",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Genetic Variants in a Haplotype Block Spanning IDE are Significantly Associated with Plasma Aβ42 Levels and Risk for Alzheimer Disease

AU - Taner, Nilufer

AU - Allen, Mariet

AU - Fadale, Daniel

AU - Scanlin, Leah

AU - Younkin, Linda

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Younkin, Steven G

PY - 2004

Y1 - 2004

N2 - Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Aβ42; 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 Aβ42 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 Aβ42 (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 Aβ42 (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.

AB - Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Aβ42; 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 Aβ42 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 Aβ42 (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 Aβ42 (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.

KW - AD

KW - Alzheimer Disease

KW - Amyloid beta

KW - APP

KW - IDE

KW - Insulin-degrading enzyme

KW - LOAD

UR - http://www.scopus.com/inward/record.url?scp=1842765688&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842765688&partnerID=8YFLogxK

U2 - 10.1002/humu.20016

DO - 10.1002/humu.20016

M3 - Article

C2 - 15024728

AN - SCOPUS:1842765688

VL - 23

SP - 334

EP - 342

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 4

ER -