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Olle Melander

Principal investigator

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Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults

Author

  • Tibor V. Varga
  • Azra Kurbasic
  • Mattias Aine
  • Pontus Eriksson
  • Ashfaq Ali
  • George Hindy
  • Stefan Gustafsson
  • Jian'an Luan
  • Dmitry Shungin
  • Yan Chen
  • Christina Alexandra Schulz
  • Peter M. Nilsson
  • Goran Hallmans
  • Iněs Barroso
  • Panos Deloukas
  • Claudia Langenberg
  • Robert A. Scott
  • Nicholas J. Wareham
  • Lars Lind
  • Erik Ingelsson
  • Olle Melander
  • Marju Orho-Melander
  • Frida Renstrom
  • Paul W. Franks

Summary, in English

Background: 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. Methods: 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. Results: 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. Conclusions: We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.

Department/s

  • Genetic and Molecular Epidemiology
  • Division of Molecular Hematology (DMH)
  • Breastcancer-genetics
  • Diabetes - Cardiovascular Disease
  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2017

Language

English

Pages

1211-1222

Publication/Series

International Journal of Epidemiology

Volume

46

Issue

4

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Medical Genetics

Keywords

  • Genetic epidemiology
  • Longitudinal analysis
  • Morbidity
  • Prospective cohort study
  • Single nucleotide polymorphism
  • Total cholesterol
  • Triglycerides

Status

Published

Research group

  • Genetic and Molecular Epidemiology
  • Diabetes - Cardiovascular Disease
  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 0300-5771