title: Estrogen receptor beta polymorphisms and cognitive performance in women: associations and modifications by genetic and environmental influences.
abstract: Genetic and environmental risk factors contribute to the pathogenesis of Alzheimer's dementia. Besides known genetic risk factors like the apolipoprotein (APO) Eε4 allele, single nuclear polymorphisms (SNPs) of the estrogen receptors (ESRs) are candidate genetic risk factors, while air pollution represents an environmental risk factor for dementia. Effects of these risk factors and their interaction were investigated in the SALIA cohort of 834 non-demented elderly women. Cognitive function was assessed by the CERAD-plus test battery. Air pollution was estimated by land use regression (LUR) models. Genotyping was carried out for nine ESR1 and ESR2 SNPs and two ApoE SNPs. Carriers of minor ESR2 alleles showed significantly reduced cognitive performance in the CERAD total score with most pronounced deficits in semantic memory (rs1256062, rs10144225, and rs2274705) and executive function (rs1256062). The minor allele effects of ESR2 were stronger in carriers of APOEε4 for the cognitive domain 'executive function' (p value of interaction 0.023 for rs1256062). The investigated ESR1 SNPs were not associated with cognition. Furthermore, we found a significant gene-environment interaction between the ESR2 SNP rs1256062 and air pollution on cognition. Carriers of two major alleles of rs1256062 were more susceptible for an air pollution-induced decrease in performance of 'figure copying' than carriers of minor alleles (p value of interaction, e.g., 0.031 for PM2.5). In conclusion, ESR2 but not ESR1 minor alleles were associated with lower cognitive performance in elderly women with an indication of a gene-gene interaction with APOEε4. We also found indications for gene-environment interactions of ESR2 with traffic-related air pollution exposure on cognitive performance.
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University Düsseldorf, Bergische Landstrasse 2, 40629, Düsseldorf, Germany. Fehsel@uni-duesseldorf.de.
authors.forename: Karin
authors.initials: K
authors.lastname: Fehsel
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Schikowski
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University Düsseldorf, Bergische Landstrasse 2, 40629, Düsseldorf, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Jänner
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hüls
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Voussoughi
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University Düsseldorf, Bergische Landstrasse 2, 40629, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schulte
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vierkötter
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.|German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Teichert
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.|German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Sugiri
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Krämer
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University Düsseldorf, Bergische Landstrasse 2, 40629, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Luckhaus
mesh_terms: D000368:Aged; D000393:Air Pollutants / Q000009:adverse effects*; D001057:Apolipoproteins E / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics*; D015331:Cohort Studies; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D018709:Statistics, Nonparametric
chemical_list: D000393:Air Pollutants; D001057:Apolipoproteins E; D047629:Estrogen Receptor beta
keywords: Air pollution; Dementia; Estrogen receptor; Gene polymorphisms; Women