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

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; Göran Hallmans; Inês Barroso; Panos Deloukas; Claudia Langenberg; Robert A Scott; Nicholas J Wareham; Lars Lind; Erik Ingelsson; Olle Melander; Marju Orho-Melander; Frida Renström; Paul W Franks

doi:10.1093/ije/dyw245

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

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, Göran Hallmans, Inês Barroso, Panos Deloukas, Claudia Langenberg, Robert A Scott, Nicholas J Wareham, Lars Lind, Erik IngelssonOlle Melander, Marju Orho-Melander, Frida Renström, Paul W Franks

13 Citations (Scopus)

Abstract

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.

Original language	English
Journal	International Journal of Epidemiology
Volume	46
Issue number	4
Pages (from-to)	1211-1222
Number of pages	12
ISSN	0300-5771
DOIs	https://doi.org/10.1093/ije/dyw245
Publication status	Published - 1 Aug 2017
Externally published	Yes

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Journal Article

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10.1093/ije/dyw245

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Varga, T. V., Kurbasic, A., Aine, M., Eriksson, P., Ali, A., Hindy, G., Gustafsson, S., Luan, J., Shungin, D., Chen, Y., Schulz, C-A., Nilsson, P. M., Hallmans, G., Barroso, I., Deloukas, P., Langenberg, C., Scott, R. A., Wareham, N. J., Lind, L., ... Franks, P. W. (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

Varga, TV, Kurbasic, A, Aine, M, Eriksson, P, Ali, A, Hindy, G, Gustafsson, S, Luan, J, Shungin, D, Chen, Y, Schulz, C-A, Nilsson, PM, Hallmans, G, Barroso, I, Deloukas, P, Langenberg, C, Scott, RA, Wareham, NJ, Lind, L, Ingelsson, E, Melander, O, Orho-Melander, M, Renström, F & Franks, PW 2017, 'Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults', International Journal of Epidemiology, vol. 46, no. 4, pp. 1211-1222. https://doi.org/10.1093/ije/dyw245

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

abstract = "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.",

keywords = "Journal Article",

author = "Varga, {Tibor V} and Azra Kurbasic and Mattias Aine and Pontus Eriksson and Ashfaq Ali and George Hindy and Stefan Gustafsson and Jian'an Luan and Dmitry Shungin and Yan Chen and Christina-Alexandra Schulz and Nilsson, {Peter M} and G{\"o}ran Hallmans and In{\^e}s Barroso and Panos Deloukas and Claudia Langenberg and Scott, {Robert A} and Wareham, {Nicholas J} and Lars Lind and Erik Ingelsson and Olle Melander and Marju Orho-Melander and Frida Renstr{\"o}m and Franks, {Paul W}",

year = "2017",

month = aug,

day = "1",

doi = "10.1093/ije/dyw245",

language = "English",

volume = "46",

pages = "1211--1222",

journal = "International Journal of Epidemiology",

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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

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 - Journal Article

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 -

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

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