TY - JOUR

T1 - Genetic determinants of long-term changes in blood lipid concentrations

T2 - 10-year follow-up of the GLACIER study

AU - Varga, Tibor V

AU - Sonestedt, Emily

AU - Shungin, Dmitry

AU - Koivula, Robert W

AU - Hallmans, Göran

AU - Escher, Stefan A

AU - Barroso, Inês

AU - Nilsson, Peter

AU - Melander, Olle

AU - Orho-Melander, Marju

AU - Renström, Frida

AU - Franks, Paul W

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - Aged

KW - Apolipoprotein A-I/genetics

KW - Apolipoproteins E/genetics

KW - Cholesterol/blood

KW - Cohort Studies

KW - Cross-Sectional Studies

KW - Female

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Life Style

KW - Longitudinal Studies

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors

KW - Surveys and Questionnaires

KW - Sweden

KW - Triglycerides/blood

U2 - 10.1371/journal.pgen.1004388

DO - 10.1371/journal.pgen.1004388

M3 - Journal article

C2 - 24922540

VL - 10

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 6

M1 - e1004388

ER -