title: Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.
abstract: The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE epsilon 4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE epsilon 4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the A beta(40) peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.
authors.affiliation: INSERM, U744, Université de Lille 2, Institut Pasteur de Lille, BP 245,1, rue du professeur Calmette, Lille cedex, France.
authors.forename: J
authors.initials: J
authors.lastname: Chapuis
authors.forename: D
authors.initials: D
authors.lastname: Hot
authors.forename: F
authors.initials: F
authors.lastname: Hansmannel
authors.forename: O
authors.initials: O
authors.lastname: Kerdraon
authors.forename: S
authors.initials: S
authors.lastname: Ferreira
authors.forename: C
authors.initials: C
authors.lastname: Hubans
authors.forename: C A
authors.initials: CA
authors.lastname: Maurage
authors.forename: L
authors.initials: L
authors.lastname: Huot
authors.forename: F
authors.initials: F
authors.lastname: Bensemain
authors.forename: G
authors.initials: G
authors.lastname: Laumet
authors.forename: A M
authors.initials: AM
authors.lastname: Ayral
authors.forename: N
authors.initials: N
authors.lastname: Fievet
authors.forename: J J
authors.initials: JJ
authors.lastname: Hauw
authors.forename: S T
authors.initials: ST
authors.lastname: DeKosky
authors.forename: Y
authors.initials: Y
authors.lastname: Lemoine
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: F
authors.initials: F
authors.lastname: Wavrant-Devrièze
authors.forename: J F
authors.initials: JF
authors.lastname: Dartigues
authors.forename: C
authors.initials: C
authors.lastname: Tzourio
authors.forename: L
authors.initials: L
authors.lastname: Buée
authors.forename: F
authors.initials: F
authors.lastname: Pasquier
authors.forename: C
authors.initials: C
authors.lastname: Berr
authors.forename: D
authors.initials: D
authors.lastname: Mann
authors.forename: C
authors.initials: C
authors.lastname: Lendon
authors.forename: A
authors.initials: A
authors.lastname: Alpérovitch
authors.forename: M I
authors.initials: MI
authors.lastname: Kamboh
authors.forename: P
authors.initials: P
authors.lastname: Amouyel
authors.forename: J C
authors.initials: JC
authors.lastname: Lambert
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D005260:Female; D005500:Follow-Up Studies; D040741:Genetic Load; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism*; D007391:International Cooperation; D008297:Male; D009447:Neuroblastoma; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)