title: The effects of two polymorphisms on p21cip1 function and their association with Alzheimer's disease in a population of European descent.
abstract: With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and Parkinson's disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson's disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer's disease, and Parkinson's disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer's disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration.
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Yates
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Amen
authors.initials: A
authors.lastname: Zafar
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Erzsebet M
authors.initials: EM
authors.lastname: Rabai
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: James B
authors.initials: JB
authors.lastname: Foxall
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Sheila
authors.initials: S
authors.lastname: Nagy
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Carl
authors.initials: C
authors.lastname: Clarke
authors.affiliation: Department of Neuropathology, University of Oxford, Level 1, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Esiri
authors.affiliation: OPTIMA, University of Oxford, Level 4, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
authors.forename: Sharon
authors.initials: S
authors.lastname: Christie
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom.
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
authors.affiliation: Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Nagy
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D017209:Apoptosis; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D018572:Disease-Free Survival; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D020641:Polymorphism, Single Nucleotide; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D044465:White People; D016875:tau Proteins / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016875:tau Proteins