title: Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.
abstract: Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids.
  
  
  
  Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N ∼ 190 000) and functional annotation for the top ranking variants.
  
  
  
  In total, 956 variants were associated (P < 0.01) with either ΔTC or ΔTG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ΔTG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 × 10-8), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 × 10-6). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P < 10-3). Of these, a variant at CAPN3 (P = 1.2 × 10-4), multiple variants at HPR (Pmin = 1.5 × 10-6) and a variant at SIX5 (P = 1.9 × 10-4) showed evidence for association with CAD.
  
  
  
  We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Tibor V
authors.initials: TV
authors.lastname: Varga
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Azra
authors.initials: A
authors.lastname: Kurbasic
authors.affiliation: Division of Oncology and Pathology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Aine
authors.affiliation: Division of Oncology and Pathology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Ali
authors.affiliation: Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: George
authors.initials: G
authors.lastname: Hindy
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.|Department of Odontology.|Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shungin
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Christina-Alexandra
authors.initials: CA
authors.lastname: Schulz
authors.affiliation: Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Metabolic Research Laboratories.|NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK.|Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
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: Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.|Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Renström
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.|Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.|Department of Nutrition, Harvard T.H Chan School of Public Health, Boston, MA, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
mesh_terms: D000328:Adult; D000368:Aged; D003324:Coronary Artery Disease / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013548:Sweden; D044465:White People / Q000235:genetics*
chemical_list: D008055:Lipids
keywords: Prospective cohort study; genetic epidemiology; longitudinal analysis; morbidity; single nucleotide polymorphism; total cholesterol; triglycerides