title: Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study.
abstract: Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0 × 10(-11) for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0 × 10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0 × 10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1 × 10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4 × 10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P ≤ 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: Tibor V
authors.initials: TV
authors.lastname: Varga
authors.affiliation: Department of Clinical Sciences, Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Emily
authors.initials: E
authors.lastname: Sonestedt
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Odontology, Umeå University, Umeå, Sweden; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shungin
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Koivula
authors.affiliation: Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Escher
authors.affiliation: NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, Skåne University Hospital, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Clinical Sciences, Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Renström
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
mesh_terms: D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008019:Life Style; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011795:Surveys and Questionnaires; D013548:Sweden; D014280:Triglycerides / Q000097:blood*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D047908:Intracellular Signaling Peptides and Proteins; C493170:TRIB1 protein, human; D014280:Triglycerides; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases