Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

Research output: Contribution to journalJournal articleResearchpeer-review

  • Anna Helgadottir
  • Gudmar Thorleifsson
  • Kristjan F Alexandersson
  • Vinicius Tragante
  • Margret Thorsteinsdottir
  • Finnur F Eiriksson
  • Solveig Gretarsdottir
  • Eythór Björnsson
  • Olafur Magnusson
  • Gardar Sveinbjornsson
  • Ingileif Jonsdottir
  • Valgerdur Steinthorsdottir
  • Egil Ferkingstad
  • Brynjar Ö Jensson
  • Hreinn Stefansson
  • Isleifur Olafsson
  • Christian Erikstrup
  • Erik Sørensen
  • Mette Nyegaard
  • Gudmundur I Eyjolfssson
  • Olof Sigurdardottir
  • Bjorn L Thorarinsson
  • Stefan E Matthiasson
  • Thora Steingrimsdottir
  • Einar S Bjornsson
  • Ragnar Danielsen
  • Folkert W Asselbergs
  • David O Arnar
  • Henrik Ullum
  • Patrick Sulem
  • Unnur Thorsteinsdottir
  • Gudmundur Thorgeirsson
  • Hilma Holm
  • Daniel F Gudbjartsson
  • Kari Stefansson

AIMS: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols.

METHODS AND RESULTS: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4).

CONCLUSIONS: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.

Original languageEnglish
JournalEuropean Heart Journal
Issue number28
Pages (from-to)2618-2628
Number of pages11
Publication statusPublished - 2020

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