Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study

• Published in: PLoS genetics Vol. 10; no. 6; p. e1004388
• Main Authors: Varga, Tibor V, Sonestedt, Emily, Shungin, Dmitry, Koivula, Robert W, Hallmans, Göran, Escher, Stefan A, Barroso, Inês, Nilsson, Peter, Melander, Olle, Orho-Melander, Marju, Renström, Frida, Franks, Paul W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2014; Public Library of Science (PLoS)
• Subjects: Age; Aged; Analysis; Antilipemic agents; Apolipoprotein A-I - genetics; Apolipoproteins; Apolipoproteins E - genetics; Biology and Life Sciences; Blood; Cardiovascular disease; Cholesterol; Cholesterol - blood; Clinical Medicine; Cohort Studies; Confidence intervals; Councils; Cross-Sectional Studies; Diabetes; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Generalized linear models; Genome-Wide Association Study; Genomes; Genotype; Glaciers; Health risk assessment; Heart; Heart attacks; Humans; Intracellular Signaling Peptides and Proteins - genetics; Klinisk medicin; Life Style; Lipids; Longitudinal Studies; Male; Medical and Health Sciences; Medical personnel; Medicin och hälsovetenskap; Medicine and Health Sciences; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Single nucleotide polymorphisms; Studies; Surveys and Questionnaires; Sweden; Triglycerides - blood; Sweden; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004388

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.