Association of HSP70 and its Co-Chaperones with Alzheimer's Disease

Article type: Research Article

Authors: Broer, Linda^a | Ikram, Mohammad Arfan^a | Schuur, Maaike^d | DeStefano, Anita L.^{e; f; g} | Bis, Joshua C.^h | Liu, Fan^a | Rivadeneira, Fernando^{a; b; k} | Uitterlinden, Andre G.^{a; b; k} | Beiser, Alexa S.^{e; f; g} | Longstreth, William T.^{i; j} | Hofman, Albert^a | Aulchenko, Yurii^a | Seshadri, Sudha^{e; f} | Fitzpatrick, Annette L.^j | Oostra, Ben A.^c | Breteler, Monique M.B.^a | van Duijn, Cornelia M.^{e; f; *}

Affiliations: [a] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands | [b] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands | [c] Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands | [d] Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands | [e] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [f] The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA | [g] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [h] Cardiovascular Health Resarch Unit and Department of Medicine, University of Washington, Seattle, WA, USA | [i] Department of Neurology, University of Washington, Seattle, WA, USA | [j] Deparment of Epidemiology, University of Washington, Seattle, WA, USA | [k] Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands

Correspondence: [*] Correspondence to: C.M. van Duijn, Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, PO-Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 7043394; Fax: +31 10 7044657; E-mail: c.vanduijn@erasmusmc.nl.

Abstract: The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

Keywords: Alzheimer's disease, genetic association studies, heat-shock proteins, prefoldin

DOI: 10.3233/JAD-2011-101560

Journal: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 93-102, 2011