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

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; Alex H Christensen; Christian Torp-Pedersen; Lars Køber; Ole B Pedersen; Christian Erikstrup; Erik Sørensen; Søren Brunak; Karina Banasik; Thomas F. Hansen; 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; Henning Bundgaard; Patrick Sulem; Unnur Thorsteinsdottir; Gudmundur Thorgeirsson; Hilma Holm; Daniel F Gudbjartsson; Kari Stefansson

doi:10.1093/eurheartj/ehaa531

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

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, Alex H Christensen, Christian Torp-Pedersen, Lars Køber, Ole B PedersenChristian Erikstrup, Erik Sørensen, Søren Brunak, Karina Banasik, Thomas F. Hansen, 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, Henning Bundgaard, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Hilma Holm, Daniel F Gudbjartsson, Kari Stefansson

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Journal	European Heart Journal
Volume	41
Issue number	28
Pages (from-to)	2618-2628
Number of pages	11
ISSN	0195-668X
DOIs	https://doi.org/10.1093/eurheartj/ehaa531
Publication status	Published - 2020

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Helgadottir, A., Thorleifsson, G., Alexandersson, K. F., Tragante, V., Thorsteinsdottir, M., Eiriksson, F. F., Gretarsdottir, S., Björnsson, E., Magnusson, O., Sveinbjornsson, G., Jonsdottir, I., Steinthorsdottir, V., Ferkingstad, E., Jensson, B. Ö., Stefansson, H., Olafsson, I., Christensen, A. H., Torp-Pedersen, C., Køber, L., ... Stefansson, K. (2020). Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease. European Heart Journal, 41(28), 2618-2628. https://doi.org/10.1093/eurheartj/ehaa531

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease. / Helgadottir, Anna; Thorleifsson, Gudmar; Alexandersson, Kristjan F; Tragante, Vinicius; Thorsteinsdottir, Margret; Eiriksson, Finnur F; Gretarsdottir, Solveig; Björnsson, Eythór; Magnusson, Olafur; Sveinbjornsson, Gardar; Jonsdottir, Ingileif; Steinthorsdottir, Valgerdur; Ferkingstad, Egil; Jensson, Brynjar Ö; Stefansson, Hreinn; Olafsson, Isleifur; Christensen, Alex H ; Torp-Pedersen, Christian ; Køber, Lars ; Pedersen, Ole B; Erikstrup, Christian; Sørensen, Erik; Brunak, Søren ; Banasik, Karina ; Hansen, Thomas F.; Nyegaard, Mette; Eyjolfssson, Gudmundur I; Sigurdardottir, Olof; Thorarinsson, Bjorn L; Matthiasson, Stefan E; Steingrimsdottir, Thora; Bjornsson, Einar S; Danielsen, Ragnar; Asselbergs, Folkert W; Arnar, David O; Ullum, Henrik; Bundgaard, Henning; Sulem, Patrick; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Holm, Hilma; Gudbjartsson, Daniel F; Stefansson, Kari.

In: European Heart Journal, Vol. 41, No. 28, 2020, p. 2618-2628.

Research output: Contribution to journal › Journal article › Research › peer-review

Helgadottir, A, Thorleifsson, G, Alexandersson, KF, Tragante, V, Thorsteinsdottir, M, Eiriksson, FF, Gretarsdottir, S, Björnsson, E, Magnusson, O, Sveinbjornsson, G, Jonsdottir, I, Steinthorsdottir, V, Ferkingstad, E, Jensson, BÖ, Stefansson, H, Olafsson, I, Christensen, AH , Torp-Pedersen, C , Køber, L , Pedersen, OB, Erikstrup, C, Sørensen, E, Brunak, S , Banasik, K , Hansen, TF, Nyegaard, M, Eyjolfssson, GI, Sigurdardottir, O, Thorarinsson, BL, Matthiasson, SE, Steingrimsdottir, T, Bjornsson, ES, Danielsen, R, Asselbergs, FW, Arnar, DO, Ullum, H, Bundgaard, H, Sulem, P, Thorsteinsdottir, U, Thorgeirsson, G, Holm, H, Gudbjartsson, DF & Stefansson, K 2020, 'Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease', European Heart Journal, vol. 41, no. 28, pp. 2618-2628. https://doi.org/10.1093/eurheartj/ehaa531

Helgadottir, Anna ; Thorleifsson, Gudmar ; Alexandersson, Kristjan F ; Tragante, Vinicius ; Thorsteinsdottir, Margret ; Eiriksson, Finnur F ; Gretarsdottir, Solveig ; Björnsson, Eythór ; Magnusson, Olafur ; Sveinbjornsson, Gardar ; Jonsdottir, Ingileif ; Steinthorsdottir, Valgerdur ; Ferkingstad, Egil ; Jensson, Brynjar Ö ; Stefansson, Hreinn ; Olafsson, Isleifur ; Christensen, Alex H ; Torp-Pedersen, Christian ; Køber, Lars ; Pedersen, Ole B ; Erikstrup, Christian ; Sørensen, Erik ; Brunak, Søren ; Banasik, Karina ; Hansen, Thomas F. ; Nyegaard, Mette ; Eyjolfssson, Gudmundur I ; Sigurdardottir, Olof ; Thorarinsson, Bjorn L ; Matthiasson, Stefan E ; Steingrimsdottir, Thora ; Bjornsson, Einar S ; Danielsen, Ragnar ; Asselbergs, Folkert W ; Arnar, David O ; Ullum, Henrik ; Bundgaard, Henning ; Sulem, Patrick ; Thorsteinsdottir, Unnur ; Thorgeirsson, Gudmundur ; Holm, Hilma ; Gudbjartsson, Daniel F ; Stefansson, Kari. / Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease. In: European Heart Journal. 2020 ; Vol. 41, No. 28. pp. 2618-2628.

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title = "Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease",

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.",

author = "Anna Helgadottir and Gudmar Thorleifsson and Alexandersson, {Kristjan F} and Vinicius Tragante and Margret Thorsteinsdottir and Eiriksson, {Finnur F} and Solveig Gretarsdottir and Eyth{\'o}r Bj{\"o}rnsson and Olafur Magnusson and Gardar Sveinbjornsson and Ingileif Jonsdottir and Valgerdur Steinthorsdottir and Egil Ferkingstad and Jensson, {Brynjar {\"O}} and Hreinn Stefansson and Isleifur Olafsson and Christensen, {Alex H} and Christian Torp-Pedersen and Lars K{\o}ber and Pedersen, {Ole B} and Christian Erikstrup and Erik S{\o}rensen and S{\o}ren Brunak and Karina Banasik and Hansen, {Thomas F.} and Mette Nyegaard and Eyjolfssson, {Gudmundur I} and Olof Sigurdardottir and Thorarinsson, {Bjorn L} and Matthiasson, {Stefan E} and Thora Steingrimsdottir and Bjornsson, {Einar S} and Ragnar Danielsen and Asselbergs, {Folkert W} and Arnar, {David O} and Henrik Ullum and Henning Bundgaard and Patrick Sulem and Unnur Thorsteinsdottir and Gudmundur Thorgeirsson and Hilma Holm and Gudbjartsson, {Daniel F} and Kari Stefansson",

year = "2020",

doi = "10.1093/eurheartj/ehaa531",

language = "English",

volume = "41",

pages = "2618--2628",

journal = "European Heart Journal",

issn = "0195-668X",

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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 -