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Int J Mol Epidemiol Genet 2012;3(1):39-47

Original Article
Interactions between PPAR-α and inflammation-related cytokine genes on the
development of Alzheimer’s disease, observed by the Epistasis Project

Reinhard Heun, Heike Kölsch, Carla A Ibrahim-Verbaas, Onofre Combarros, Yurii S Aulchenko, Monique Breteler, Maaike
Schuur, Cornelia M van Duijn, Naomi Hammond, Olivia Belbin, Mario Cortina-Borja, Gordon K Wilcock, Kristelle Brown, Rachel
Barber, Patrick G Kehoe, Eliecer Coto, Victoria Alvarez, Michael G Lehmann, Panos Deloukas, Ignacio Mateo, Kevin Morgan,
Donald R Warden, A David Smith, Donald J Lehmann

Department of Psychiatry, University of Bonn, Bonn, Germany; Department of Psychiatry, Royal Derby Hospital, Uttoxeter Road,
Derby DE22 3WQ, UK; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands;
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Neurology Service and
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla
University Hospital (University of Cantabria), 39008 Santander, Spain; The Wellcome Trust Sanger Institute, Hinxton,
Cambridge CB10 1SA, UK; School of Molecular Medical Sciences, Institute of Genetics, University of Nottingham, Queens
Medical Centre, Nottingham NG7 2UH, UK; MRC Centre of Epidemiology for Child Health, Institute of Child Health, University
College London, 30 Guilford Street, London WC1N 1EH, UK; Nuffield Department of Medicine, University of Oxford, Level 4,
John Radcliffe Hospital, Oxford OX3 9DU, UK; Dementia Research Group, Institute of Clinical Neurosciences, University of
Bristol, Frenchay Hospital, Frenchay Bristol, BS16 1LE, UK; Genética Molecular, Hospital Central de Asturias, Oviedo, Spain;
Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Mansfield Road, Oxford
OX1 3QT, UK.

Received December 24, 2011; Accepted February 22, 2012; Epub February 23, 2012; Published February 28, 2012

Abstract: Objective: Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer’s disease (AD). Variations in
genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified
relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We
investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1β, IL-6, and IL-10 may interact to
increase AD risk. Methods: The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single
nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by
fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele
(APOEε4). Adjusted synergy factors were derived from interaction terms (p<0.05 two-sided). Results: We observed four
significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There
were no significant interactions between PPARA and IL6. Conclusions: In addition to an association of the PPARA L162V
polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and
IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when
assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending
on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.(IJMEG1112002).

Keywords: AD, genetics, epistasis, inflammation, interleukin, steroid receptors, PPAR-alpha, sporadic, genetic interaction


Address all correspondence to:
Professor Reinhard Heun
Department of Psychiatry
Royal Derby Hospital
Uttoxeter Road, Derby DE22 3WQ, UK.
E-mail: heun@gmx.com