Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults
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Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults. / Varga, Tibor V; Kurbasic, Azra; Aine, Mattias; Eriksson, Pontus; Ali, Ashfaq; Hindy, George; Gustafsson, Stefan; Luan, Jian'an; Shungin, Dmitry; Chen, Yan; Schulz, Christina-Alexandra; Nilsson, Peter M; Hallmans, Göran; Barroso, Inês; Deloukas, Panos; Langenberg, Claudia; Scott, Robert A; Wareham, Nicholas J; Lind, Lars; Ingelsson, Erik; Melander, Olle; Orho-Melander, Marju; Renström, Frida; Franks, Paul W.
In: International Journal of Epidemiology, Vol. 46, No. 4, 01.08.2017, p. 1211-1222.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults
AU - Varga, Tibor V
AU - Kurbasic, Azra
AU - Aine, Mattias
AU - Eriksson, Pontus
AU - Ali, Ashfaq
AU - Hindy, George
AU - Gustafsson, Stefan
AU - Luan, Jian'an
AU - Shungin, Dmitry
AU - Chen, Yan
AU - Schulz, Christina-Alexandra
AU - Nilsson, Peter M
AU - Hallmans, Göran
AU - Barroso, Inês
AU - Deloukas, Panos
AU - Langenberg, Claudia
AU - Scott, Robert A
AU - Wareham, Nicholas J
AU - Lind, Lars
AU - Ingelsson, Erik
AU - Melander, Olle
AU - Orho-Melander, Marju
AU - Renström, Frida
AU - Franks, Paul W
N1 - © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Coronary Artery Disease/genetics
KW - Cross-Sectional Studies
KW - European Continental Ancestry Group/genetics
KW - Female
KW - Genetic Loci
KW - Genome-Wide Association Study
KW - Genotype
KW - Humans
KW - Lipids/blood
KW - Male
KW - Meta-Analysis as Topic
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Prospective Studies
KW - Sweden
U2 - 10.1093/ije/dyw245
DO - 10.1093/ije/dyw245
M3 - Journal article
C2 - 27864399
VL - 46
SP - 1211
EP - 1222
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
SN - 0300-5771
IS - 4
ER -
ID: 242836904