Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.
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Nilsson, Peter M
Scott, Robert A
International journal of epidemiology
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Varga, T. V., Kurbasic, A., Aine, M., Eriksson, P., Ali, A., Hindy, G., Gustafsson, S., et al. (2017). Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.. International journal of epidemiology, 46 (4), 1211-1222. https://doi.org/10.1093/ije/dyw245
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.
Humans, Lipids, Prospective Studies, Cross-Sectional Studies, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Sweden, Female, Male, Coronary Artery Disease, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci
Medical Research Council (5PV0E)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
Medical Research Council (G0701863)
Medical Research Council (MC_U106179471)
External DOI: https://doi.org/10.1093/ije/dyw245
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266412