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

ABSTRACT: 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.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 (?TC) and triglycerides (?TG). 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.In total, 956 variants were associated (P < 0.01) with either ?TC or ?TG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ?TG 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 ?TC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ?TC and for ?TG, 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.We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.

SUBMITTER: Varga TV 

PROVIDER: S-EPMC5837581 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature