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Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease

Molecular Psychiatry volume 14, pages 1004–1016 (2009)Cite this article

Abstract

The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the ɛ4 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 ɛ4 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 ɛ4 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 Aβ40 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.

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Acknowledgements

We thank Jo Ann Cahn for her helpful contribution in writing of the manuscript and Dr Morisada Hayakawa for providing us the monoclonal ST2 antibody and Ryan Minster for technical support. Julien Chapuis was supported by the Ministère de l’enseignement supérieur et de la Recherche (MESR). Franck Hansmannel was supported by the Alzheimer's association (Grant IIRG-06-25487). Faiza Bensemain was supported by the France Alzheimer Association. Geoffroy Laumet was supported by the Pasteur Institute of Lille and the region Nord-Pas de Calais. This study was funded by Genoscreen, INSERM (ATC-vieillissement), the Pasteur Institute of Lille, the genopole of Lille, the CPER-neuroscience and the US National Institute on Aging Grants AG13672 and AG05133 (I.K. and S.T.D.). The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen–Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C-Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the jont French Ministry of Research/INSERM ‘Cohortes et collections de données biologiques’ programme. Lille Génopôle received an unconditional grant from Eisai.

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Authors and Affiliations

  1. INSERM, U744, Université de Lille 2, Institut Pasteur de Lille, BP 245,1, rue du professeur Calmette, Lille cedex, France

    J Chapuis, F Hansmannel, F Bensemain, G Laumet, A M Ayral, N Fievet, P Amouyel & J C Lambert

  2. Laboratoire des Biopuces, Institut Pasteur de Lille, BP 245,1, rue du professeur Calmette, Lille cedex, France

    D Hot, L Huot & Y Lemoine

  3. INSERM, U837, Université de Lille 2, 1 Place Verdun, Lille cedex, France

    O Kerdraon, C A Maurage & L Buée

  4. Génoscreen, BP 245,1, rue du professeur Calmette, Lille cedex, France

    S Ferreira & C Hubans

  5. INSERM, IFR70, hôpital de la Pitié-Salpêtrière, laboratoire de Neuropathologie, 47 Bd de l'Hopital, Paris, France

    J J Hauw

  6. Department of Human Genetics and Alzheimer's Disease Research Centre, University of Pittsburgh, A300 Crabtree Hall, GSPH 130 Desoto Street, Pittsburgh, PA, USA

    S T DeKosky & M I Kamboh

  7. Department of Neuropathology and Neuroscience, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo, Japan

    T Iwatsubo

  8. Laboratory of Neurogenetics, National Institute on Aging, NIH, Bldg. 35, Bethesda, MD, USA

    F Wavrant-Devrièze

  9. INSERM, U593, Université Victor Segalen, Bordeaux, France

    J F Dartigues

  10. INSERM, Paris, France

    C Tzourio & A Alpérovitch

  11. Department of Neurology, EA2391, Memory Clinic, University Hospital of Lille, CHU Hôpital Roger Salengro rue du professeur Emile Laine, Lille cedex, France

    F Pasquier

  12. INSERM, U888, Université de Montpellier I, Hôpital La Colombière, Pavillon 42, 39 Avenue Charles Flahault BP 34493, Montpellier Cedex, France

    C Berr

  13. School of Translational Medicine, University of Manchester, Hope Hospital, Salford, UK

    D Mann

  14. Molecular Psychiatry Group, Queensland Institute of Medical Research, PO Royal Brisbane Hospital Queensland, Brisbane, Australia

    C Lendon

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  1. J Chapuis
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Correspondence to J C Lambert.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Chapuis, J., Hot, D., Hansmannel, F. et al. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Mol Psychiatry 14, 1004–1016 (2009). https://doi.org/10.1038/mp.2009.10

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