ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease

PLoS Genet. 2021 Apr 28;17(4):e1009501. doi: 10.1371/journal.pgen.1009501. eCollection 2021 Apr.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angiopoietin-Like Protein 8
  • Angiopoietin-like Proteins / genetics*
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / genetics
  • Coronary Artery Disease / pathology
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / pathology
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / genetics
  • Dyslipidemias / pathology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Male
  • Middle Aged
  • Peptide Hormones / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Triglycerides / blood

Substances

  • ANGPTL8 protein, human
  • Angiopoietin-Like Protein 8
  • Angiopoietin-like Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Peptide Hormones
  • Triglycerides

Grants and funding

The FinnGen project is funded by two grants from Business Finland (https://www.businessfinland.fi/) (HUS 4685/31/2016 and UH 4386/31/2016) and by the following industry partners: AbbVie Inc, AstraZeneca UK Ltd, Biogen MA Inc, Celgene Corporation, Celgene International II Sàrl, Genentech Inc, Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline, Sanofi, Maze Therapeutics Inc., Janssen Biotech Inc and Novartis AG. This work was supported by the Sigrid Jusélius Foundation (https://sigridjuselius.fi/en/) (to S.R., A.P.); University of Helsinki HiLIFE (https://www.helsinki.fi/en/helsinki-institute-of-life-science) Fellow grants 2017-2020 and HiLIFE Grand Challenge (to S.R.); Academy of Finland (https://www.aka.fi/en) Center of Excellence in Complex Disease Genetics (grant number 312062 and 336820 to S.R., 312074 and 336824 to A.P., 312075 and 336821 to M.J.D.); Academy of Finland (grant number 285380 to S.R., 128650 to A.P., 321356 to A.S.H.); Foundation and the Horizon 2020 Research and Innovation Programme (https://ec.europa.eu/programmes/horizon2020/en) (grant number 101016775 [INTERVENE] to S.R., grant number 667301 [COSYN] to A.P.); The Finnish Foundation for Cardiovascular Research (https://www.sydantutkimussaatio.fi/en/foundation) (to S.R., A.P., V.S.); Precision Health Scholars Award from the University of Michigan Medical School (https://precisionhealth.umich.edu/tools-resources/grants/u-m-precision-health-scholars-awards/2018-scholars-awards/) (to I.S.); Doctoral Programme in Population Health, University of Helsinki (https://www.helsinki.fi/en/research/doctoral-education/doctoral-schools-and-programmes/doctoral-school-in-health-sciences/doctoral-programme-in-population-health) (to P.H., T.K.); Emil Aaltonen Foundation (https://emilaaltonen.fi/) (to P.H.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.