TY - JOUR
T1 - Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease
AU - Helgadottir, Anna
AU - Thorleifsson, Gudmar
AU - Alexandersson, Kristjan F
AU - Tragante, Vinicius
AU - Thorsteinsdottir, Margret
AU - Eiriksson, Finnur F
AU - Gretarsdottir, Solveig
AU - Björnsson, Eythór
AU - Magnusson, Olafur
AU - Sveinbjornsson, Gardar
AU - Jonsdottir, Ingileif
AU - Steinthorsdottir, Valgerdur
AU - Ferkingstad, Egil
AU - Jensson, Brynjar Ö
AU - Stefansson, Hreinn
AU - Olafsson, Isleifur
AU - Christensen, Alex H
AU - Torp-Pedersen, Christian
AU - Køber, Lars
AU - Pedersen, Ole B
AU - Erikstrup, Christian
AU - Sørensen, Erik
AU - Brunak, Søren
AU - Banasik, Karina
AU - Hansen, Thomas F.
AU - Nyegaard, Mette
AU - Eyjolfssson, Gudmundur I
AU - Sigurdardottir, Olof
AU - Thorarinsson, Bjorn L
AU - Matthiasson, Stefan E
AU - Steingrimsdottir, Thora
AU - Bjornsson, Einar S
AU - Danielsen, Ragnar
AU - Asselbergs, Folkert W
AU - Arnar, David O
AU - Ullum, Henrik
AU - Bundgaard, Henning
AU - Sulem, Patrick
AU - Thorsteinsdottir, Unnur
AU - Thorgeirsson, Gudmundur
AU - Holm, Hilma
AU - Gudbjartsson, Daniel F
AU - Stefansson, Kari
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1093/eurheartj/ehaa531
DO - 10.1093/eurheartj/ehaa531
M3 - Journal article
C2 - 32702746
VL - 41
SP - 2618
EP - 2628
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 28
ER -