title: The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project.
abstract: Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.
authors.affiliation: Human Genetics Research, Queens Medical Centre, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas(CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), Santander, Spain.
authors.forename: Onofre
authors.initials: O
authors.lastname: Combarros
authors.affiliation: MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Cortina-Borja
authors.affiliation: Genomics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Helen T
authors.initials: HT
authors.lastname: Butler
authors.affiliation: 1] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands [2] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Ibrahim-Verbaas
authors.affiliation: 1] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands [2] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
authors.forename: Renée F A G
authors.initials: RF
authors.lastname: de Bruijn
authors.affiliation: Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koudstaal
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: 1] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands [2] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands [3] Department of Radiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas(CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), Santander, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mateo
authors.affiliation: Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas(CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), Santander, Spain.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sánchez-Juan
authors.affiliation: Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lehmann
authors.affiliation: 1] Department of Psychiatry, University of Bonn, Bonn, Germany [2] Department of Psychiatry, Royal Derby Hospital, Derby, UK.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hammond
authors.affiliation: Genética Molecular, Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.affiliation: Genética Molecular, Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.affiliation: Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Frenchay Bristol, UK.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.affiliation: Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Frenchay Bristol, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Barber
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Level 4, John Radcliffe Hospital, Oxford, UK.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Wilcock
authors.affiliation: Human Genetics Research, Queens Medical Centre, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Kristelle
authors.initials: K
authors.lastname: Brown
authors.affiliation: Human Genetics Research, Queens Medical Centre, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.affiliation: Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Warden
authors.affiliation: Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK.
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
authors.affiliation: Human Genetics Research, Queens Medical Centre, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.affiliation: Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Lehmann
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D001141:Aromatase / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012727:Sex Characteristics
chemical_list: C508609:IL10 protein, human; D016753:Interleukin-10; D001141:Aromatase; C561410:CYP19A1 protein, human