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 Citationer (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.

OriginalsprogEngelsk
TidsskriftInternational Journal of Epidemiology
Vol/bind46
Udgave nummer4
Sider (fra-til)1211-1222
Antal sider12
ISSN0300-5771
DOI
StatusUdgivet - 1 aug. 2017
Udgivet eksterntJa

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