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
Abstract 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...
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BMC
2018-03-01
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| Series: | BMC Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12916-018-1029-3 |
| _version_ | 1818652043945967616 |
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| author | Liv Tybjærg Nordestgaard Anne Tybjærg-Hansen Katrine Laura Rasmussen Børge G. Nordestgaard Ruth Frikke-Schmidt |
| author_facet | Liv Tybjærg Nordestgaard Anne Tybjærg-Hansen Katrine Laura Rasmussen Børge G. Nordestgaard Ruth Frikke-Schmidt |
| author_sort | Liv Tybjærg Nordestgaard |
| collection | DOAJ |
| description | Abstract 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. |
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| language | English |
| last_indexed | 2024-12-17T02:15:44Z |
| publishDate | 2018-03-01 |
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| spelling | doaj.art-ae5f0ad36d6b4a0bb4579a30d05250642022-12-21T22:07:25ZengBMCBMC Medicine1741-70152018-03-0116111110.1186/s12916-018-1029-3Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individualsLiv Tybjærg Nordestgaard0Anne Tybjærg-Hansen1Katrine Laura Rasmussen2Børge G. Nordestgaard3Ruth Frikke-Schmidt4Department of Clinical Biochemistry, RigshospitaletDepartment of Clinical Biochemistry, RigshospitaletDepartment of Clinical Biochemistry, RigshospitaletThe Copenhagen City Heart Study, Frederiksberg HospitalDepartment of Clinical Biochemistry, RigshospitaletAbstract 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.http://link.springer.com/article/10.1186/s12916-018-1029-3ClusterinApolipoprotein EAlzheimer’s diseaseVascular dementiaIschemic cerebrovascular diseaseIschemic heart disease |
| spellingShingle | Liv Tybjærg Nordestgaard Anne Tybjærg-Hansen Katrine Laura Rasmussen Børge G. Nordestgaard Ruth Frikke-Schmidt 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 BMC Medicine Clusterin Apolipoprotein E Alzheimer’s disease Vascular dementia Ischemic cerebrovascular disease Ischemic heart disease |
| 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 | Clusterin Apolipoprotein E Alzheimer’s disease Vascular dementia Ischemic cerebrovascular disease Ischemic heart disease |
| url | http://link.springer.com/article/10.1186/s12916-018-1029-3 |
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