TY - JOUR

T1 - Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population

T2 - Cohort studies and meta-analyses of 362,338 individuals

AU - Nordestgaard, Liv Tybjærg

AU - Tybjærg-Hansen, Anne

AU - Rasmussen, Katrine Laura

AU - Nordestgaard, Børge G.

AU - Frikke-Schmidt, Ruth

PY - 2018

Y1 - 2018

N2 - 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 4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the 4 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.

AB - 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 4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the 4 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.

KW - Alzheimer's disease

KW - Apolipoprotein E

KW - Clusterin

KW - Cohort study

KW - Ischemic cerebrovascular disease

KW - Ischemic heart disease

KW - Meta-analysis

KW - Vascular dementia

U2 - 10.1186/s12916-018-1029-3

DO - 10.1186/s12916-018-1029-3

M3 - Journal article

C2 - 29534716

AN - SCOPUS:85043476639

VL - 16

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

M1 - 39

ER -