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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. LU ; Kurbasic, Azra LU ; Aine, Mattias LU ; Eriksson, Pontus LU ; Ali, Ashfaq; Hindy, George LU ; Gustafsson, Stefan; Luan, Jian'an; Shungin, Dmitry LU and Chen, Yan LU , et al. (2017) In International Journal of Epidemiology 46(4). p.1211-1222
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... (More)

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.

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keywords
Genetic epidemiology, Longitudinal analysis, Morbidity, Prospective cohort study, Single nucleotide polymorphism, Total cholesterol, Triglycerides
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International Journal of Epidemiology
volume
46
issue
4
pages
12 pages
publisher
Oxford University Press
external identifiers
  • scopus:85030465803
ISSN
0300-5771
DOI
10.1093/ije/dyw245
language
English
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yes
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1cf44389-a077-45e9-ab0e-2b4da333af5b
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2018-02-14 15:06:58
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2018-10-28 12:50:12
@article{1cf44389-a077-45e9-ab0e-2b4da333af5b,
  abstract     = {<p>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 (N<sub>max</sub> = 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; N<sub>max</sub> = 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 &lt; 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 &lt; 5×10<sup>-8</sup>), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P &lt; 1.7 × 10<sup>-6</sup>). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P &lt; 1.7 × 10<sup>-6</sup>). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P &lt; 10<sup>-3</sup>). Of these, a variant at CAPN3 (P = 1.2 × 10<sup>-4</sup>), multiple variants at HPR (P<sub>min</sub> = 1.5 × 10<sup>-6</sup>) and a variant at SIX5 (P = 1.9 × 10<sup>-4</sup>) 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.</p>},
  author       = {Varga, Tibor V. and Kurbasic, Azra and Aine, Mattias and Eriksson, Pontus and Ali, Ashfaq and Hindy, George and Gustafsson, Stefan and Luan, Jian'an and Shungin, Dmitry and Chen, Yan and Schulz, Christina Alexandra and Nilsson, Peter M. and Hallmans, Goran and Barroso, Iněs and Deloukas, Panos and Langenberg, Claudia and Scott, Robert A. and Wareham, Nicholas J. and Lind, Lars and Ingelsson, Erik and Melander, Olle and Orho-Melander, Marju and Renstrom, Frida and Franks, Paul W.},
  issn         = {0300-5771},
  keyword      = {Genetic epidemiology,Longitudinal analysis,Morbidity,Prospective cohort study,Single nucleotide polymorphism,Total cholesterol,Triglycerides},
  language     = {eng},
  number       = {4},
  pages        = {1211--1222},
  publisher    = {Oxford University Press},
  series       = {International Journal of Epidemiology},
  title        = {Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults},
  url          = {http://dx.doi.org/10.1093/ije/dyw245},
  volume       = {46},
  year         = {2017},
}