Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.
PMID 27864399 | PMCID PMC5837581 | DOI 10.1093/ije/dyw245 · International journal of epidemiology · 2017
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.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | APOE | “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).” | 0.98 | hgnc_dict_v1 |
| gene | APOA1 | “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).” | 0.98 | hgnc_dict_v1 |
| gene | DOCK7 | “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).” | 0.98 | hgnc_dict_v1 |
| gene | SYNE1 | “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).” | 0.98 | hgnc_dict_v1 |
| gene | KCNIP1 | “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).” | 0.98 | hgnc_dict_v1 |
| gene | CAPN3 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | HPR | “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.” | 0.98 | hgnc_dict_v1 |
| gene | SIX5 | “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.” | 0.98 | hgnc_dict_v1 |
| phenotype | coronary artery disease | “Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.” | 0.98 | phenotype_alias_lexicon_v2 |
| population | Population | “Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication.” | 0.80 | saudi_context_rules_v1 |
| variant | rs7412 | “The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6).” | 0.90 | hgvs_regex_v1 |