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. 2020 Jul 21;41(28):2618-2628.
doi: 10.1093/eurheartj/ehaa531.

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

Anna Helgadottir  1 , Gudmar Thorleifsson  1 , Kristjan F Alexandersson  1 , Vinicius Tragante  1   2 , Margret Thorsteinsdottir  3   4 , Finnur F Eiriksson  3 , Solveig Gretarsdottir  1 , Eythór Björnsson  1   5   6 , Olafur Magnusson  1 , Gardar Sveinbjornsson  1 , Ingileif Jonsdottir  1   6 , Valgerdur Steinthorsdottir  1 , Egil Ferkingstad  1 , Brynjar Ö Jensson  1 , Hreinn Stefansson  1 , Isleifur Olafsson  7 , Alex H Christensen  8 , Christian Torp-Pedersen  9   10 , Lars Køber  11 , Ole B Pedersen  12   13 , Christian Erikstrup  14 , Erik Sørensen  15 , Søren Brunak  16 , Karina Banasik  16 , Thomas F Hansen  16   17   18 , Mette Nyegaard  19 , Gudmundur I Eyjolfssson  20 , Olof Sigurdardottir  21 , Bjorn L Thorarinsson  22 , Stefan E Matthiasson  23 , Thora Steingrimsdottir  6   24 , Einar S Bjornsson  5   6 , Ragnar Danielsen  25 , Folkert W Asselbergs  2   26   27 , David O Arnar  1   6   25 , Henrik Ullum  15 , Henning Bundgaard  11 , Patrick Sulem  1 , Unnur Thorsteinsdottir  1   6 , Gudmundur Thorgeirsson  1   6   25 , Hilma Holm  1 , Daniel F Gudbjartsson  1   28 , Kari Stefansson  1   6
Affiliations

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

Anna Helgadottir et al. Eur Heart J. .

Abstract

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.

Keywords: ABCG5/8; Absorption; Dietary cholesterol; Genetics; Phytosterols.

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Figures

Figure 1
Figure 1
A schematic representation of sterol transport in the intestine and liver. Dietary cholesterol and non-cholesterol sterols are transported from the intestinal lumen into enterocytes via NPC1L1.While approximately 50–60% of the cholesterol that has entered the enterocytes is taken up into the circulation, the majority of phytosterols are pumped back into the intestinal lumen by ABCG5/8. In addition to excreting phytosterols, the hepatic ABCG5/8 transporters have a major role in removing cholesterol from the body. Decreased ABCG5/8 function in the liver reduces gallstone risk through diminished cholesterol saturation in bile. Phytosterols in the diet are believed to attenuate the pool of absorbable cholesterol by displacing cholesterol from intestinal micelles.
Figure 2
Figure 2
A schematic representation of the ABCG5/8 variant associations.
Figure 3
Figure 3
The relationship between variant effects on non-high-density lipoprotein cholesterol and stigmasterol. The crosses show 95% confidence intervals. SD, standard deviation units. The red (for ABCG5/8 variants) and black (for variants outside ABCG5/8 locus) lines are the best lines fitting the stigmasterol effects for non-high-density lipoprotein cholesterol variants using weighted regression with one over standard error squared as weights. The grey-shaded area around the line is the 95% confidence interval. NPC1L1 variants are plotted in blue. See data in Supplementary material online, Table S7C and G.
Take home figure
Take home figure
Genetic analysis using ABCG5/8 variants as instruments indicates that both dietary cholesterol and phytosterols contribute directly to atherogenesis.
None
See this image and copyright information in PMC

Comment in

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