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Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals

BACKGROUND: Clusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer’s disease, and may play add...

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Autores principales: Nordestgaard, Liv Tybjærg, Tybjærg-Hansen, Anne, Rasmussen, Katrine Laura, Nordestgaard, Børge G., Frikke-Schmidt, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851250/
https://www.ncbi.nlm.nih.gov/pubmed/29534716
http://dx.doi.org/10.1186/s12916-018-1029-3
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author Nordestgaard, Liv Tybjærg
Tybjærg-Hansen, Anne
Rasmussen, Katrine Laura
Nordestgaard, Børge G.
Frikke-Schmidt, Ruth
author_facet Nordestgaard, Liv Tybjærg
Tybjærg-Hansen, Anne
Rasmussen, Katrine Laura
Nordestgaard, Børge G.
Frikke-Schmidt, Ruth
author_sort Nordestgaard, Liv Tybjærg
collection PubMed
description BACKGROUND: Clusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer’s disease, and may play additional roles in atherosclerosis pathogenesis. We tested whether genetic variation in CLU was associated with either Alzheimer’s disease or atherosclerosis-related diseases. METHODS: We studied individual data on 103,987 participants from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). We genotyped a common CLU variant (rs9331896) and two common APOE variants (rs7412 and rs429358), defining the ε2, ε3, and ε4, alleles in CGPS and CCHS. All individuals in the CGPS and CCHS cohorts were followed from study inclusion to occurrence of event, death, emigration, or until 10 November 2014, whichever came first. Summary consortia data on 258,351 individuals from the International Genomics of Alzheimer’s Project (IGAP) and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics and 1000-Genomes-based genome-wide association studies (CARDIoGRAMplusC4D) were used in meta-analyses. RESULTS: In CGPS and CCHS, multifactorially adjusted hazard ratios for Alzheimer’s disease, all dementia, vascular dementia, ischemic cerebrovascular disease, and ischemic heart disease were 1.18 (1.07–1.30), 1.09 (1.02–1.17), 0.96 (0.80–1.17), 1.02 (0.97–1.07), and 0.97 (0.93–1.01) per T allele, respectively. Multifactorially adjusted hazard ratios for Alzheimer’s disease and all dementia were 2.72 (2.45–3.01) and 2.21 (2.05–2.38) for the APOE ɛ4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the ɛ4 allele) in APOE in predicting Alzheimer’s disease or all dementia (P = 0.39 and P = 0.21). In a meta-analysis including consortium data, the overall fixed- and random-effects odds ratios for Alzheimer’s disease per T allele were 1.16 (1.13–1.18) (I(2) = 0.0%; P for heterogeneity = 0.89). CONCLUSIONS: A common variant in CLU was associated with a high risk of Alzheimer’s disease and all dementia in the general population but not with vascular dementia or ischemic vascular disease. Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative ε4 allele, and several subtypes of dementia and atherosclerosis-related endpoints. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12916-018-1029-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-58512502018-03-21 Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals Nordestgaard, Liv Tybjærg Tybjærg-Hansen, Anne Rasmussen, Katrine Laura Nordestgaard, Børge G. Frikke-Schmidt, Ruth BMC Med Research Article BACKGROUND: Clusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer’s disease, and may play additional roles in atherosclerosis pathogenesis. We tested whether genetic variation in CLU was associated with either Alzheimer’s disease or atherosclerosis-related diseases. METHODS: We studied individual data on 103,987 participants from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). We genotyped a common CLU variant (rs9331896) and two common APOE variants (rs7412 and rs429358), defining the ε2, ε3, and ε4, alleles in CGPS and CCHS. All individuals in the CGPS and CCHS cohorts were followed from study inclusion to occurrence of event, death, emigration, or until 10 November 2014, whichever came first. Summary consortia data on 258,351 individuals from the International Genomics of Alzheimer’s Project (IGAP) and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics and 1000-Genomes-based genome-wide association studies (CARDIoGRAMplusC4D) were used in meta-analyses. RESULTS: In CGPS and CCHS, multifactorially adjusted hazard ratios for Alzheimer’s disease, all dementia, vascular dementia, ischemic cerebrovascular disease, and ischemic heart disease were 1.18 (1.07–1.30), 1.09 (1.02–1.17), 0.96 (0.80–1.17), 1.02 (0.97–1.07), and 0.97 (0.93–1.01) per T allele, respectively. Multifactorially adjusted hazard ratios for Alzheimer’s disease and all dementia were 2.72 (2.45–3.01) and 2.21 (2.05–2.38) for the APOE ɛ4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the ɛ4 allele) in APOE in predicting Alzheimer’s disease or all dementia (P = 0.39 and P = 0.21). In a meta-analysis including consortium data, the overall fixed- and random-effects odds ratios for Alzheimer’s disease per T allele were 1.16 (1.13–1.18) (I(2) = 0.0%; P for heterogeneity = 0.89). CONCLUSIONS: A common variant in CLU was associated with a high risk of Alzheimer’s disease and all dementia in the general population but not with vascular dementia or ischemic vascular disease. Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative ε4 allele, and several subtypes of dementia and atherosclerosis-related endpoints. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12916-018-1029-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-14 /pmc/articles/PMC5851250/ /pubmed/29534716 http://dx.doi.org/10.1186/s12916-018-1029-3 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Nordestgaard, Liv Tybjærg
Tybjærg-Hansen, Anne
Rasmussen, Katrine Laura
Nordestgaard, Børge G.
Frikke-Schmidt, Ruth
Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
title Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
title_full Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
title_fullStr Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
title_full_unstemmed Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
title_short Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
title_sort genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851250/
https://www.ncbi.nlm.nih.gov/pubmed/29534716
http://dx.doi.org/10.1186/s12916-018-1029-3
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