ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease.
Aged
Angiopoietin-Like Protein 8
Angiopoietin-like Proteins
/ genetics
Coronary Artery Disease
/ blood
Diabetes Mellitus, Type 2
/ blood
Dyslipidemias
/ blood
Female
Genetic Predisposition to Disease
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/ administration & dosage
Male
Middle Aged
Peptide Hormones
/ genetics
Polymorphism, Single Nucleotide
/ genetics
Risk Factors
Triglycerides
/ blood
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
04
08
2020
accepted:
19
03
2021
revised:
10
05
2021
pubmed:
29
4
2021
medline:
26
8
2021
entrez:
28
4
2021
Statut:
epublish
Résumé
Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10-9) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10-9). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60-0.81], P = 2.2 × 10-6) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37-0.76], P = 4.5 × 10-4) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40-0.68], P = 1.7 × 10-6) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.
Identifiants
pubmed: 33909604
doi: 10.1371/journal.pgen.1009501
pii: PGENETICS-D-20-01113
pmc: PMC8109807
doi:
Substances chimiques
ANGPTL8 protein, human
0
Angiopoietin-Like Protein 8
0
Angiopoietin-like Proteins
0
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Peptide Hormones
0
Triglycerides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009501Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests: V.S. has consulted for Novo Nordisk and Sanofi and received honoraria from these companies (unrelated to the present study). He also has ongoing research collaboration with Bayer Ltd. (unrelated to the present study). A.P. is a member of the Pfizer Genetics Scientific Advisory Panel. The remaining authors declared no relevant competing interests.
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