Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Markus Scholz; Katrin Horn; Janne Pott; Arnd Gross; Marcus E Kleber; Graciela E Delgado; Pashupati Prasad Mishra; Holger Kirsten; Christian Gieger; Martina Müller-Nurasyid; Anke Tönjes; Peter Kovacs; Terho Lehtimäki; Olli Raitakari; Mika Kähönen; Helena Gylling; Ronny Baber; Berend Isermann; Michael Stumvoll; Markus Loeffler; Winfried März; Thomas Meitinger; Annette Peters; Joachim Thiery; Daniel Teupser; Uta Ceglarek

doi:10.1038/s41467-021-27706-6

Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Markus Scholz, Katrin Horn, Janne Pott, Arnd Gross, Marcus E Kleber, Graciela E Delgado, Pashupati Prasad Mishra, Holger Kirsten, Christian Gieger, Martina Müller-Nurasyid, Anke Tönjes, Peter Kovacs, Terho Lehtimäki, Olli Raitakari, Mika Kähönen, Helena Gylling, Ronny Baber, Berend Isermann, Michael Stumvoll, Markus LoefflerWinfried März, Thomas Meitinger, Annette Peters, Joachim Thiery, Daniel Teupser, Uta Ceglarek

Department of Clinical Chemistry

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Abstract

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.

Original language	English
Article number	143
Number of pages	12
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-021-27706-6
Publication status	Published - 10 Jan 2022
Publication type	A1 Journal article-refereed

Keywords

ABO Blood-Group System/blood
ATP Binding Cassette Transporter, Subfamily G, Member 5/blood
ATP Binding Cassette Transporter, Subfamily G, Member 8/blood
Adult
Apolipoproteins E/blood
Cholesterol/blood
Coronary Artery Disease/blood
Female
Gene Expression Regulation
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Hydroxymethylglutaryl CoA Reductases/blood
Lipase/blood
Lipid Metabolism/genetics
Lipoproteins/blood
Male
Membrane Transport Proteins/blood
Mendelian Randomization Analysis
Multifactorial Inheritance
Phytosterols/blood
Polymorphism, Single Nucleotide
Scavenger Receptors, Class B/blood

Publication forum classification

Publication forum level 3

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-27706-6Licence: CC BY

s41467-021-27706-6Final published version, 1.69 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202205185057Licence: CC BY

Cite this

Scholz, M., Horn, K., Pott, J., Gross, A., Kleber, M. E., Delgado, G. E., Mishra, P. P., Kirsten, H., Gieger, C., Müller-Nurasyid, M., Tönjes, A., Kovacs, P., Lehtimäki, T., Raitakari, O., Kähönen, M., Gylling, H., Baber, R., Isermann, B., Stumvoll, M., ... Ceglarek, U. (2022). Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis. Nature Communications, 13, Article 143. https://doi.org/10.1038/s41467-021-27706-6

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title = "Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis",

abstract = "Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.",

keywords = "ABO Blood-Group System/blood, ATP Binding Cassette Transporter, Subfamily G, Member 5/blood, ATP Binding Cassette Transporter, Subfamily G, Member 8/blood, Adult, Apolipoproteins E/blood, Cholesterol/blood, Coronary Artery Disease/blood, Female, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl CoA Reductases/blood, Lipase/blood, Lipid Metabolism/genetics, Lipoproteins/blood, Male, Membrane Transport Proteins/blood, Mendelian Randomization Analysis, Multifactorial Inheritance, Phytosterols/blood, Polymorphism, Single Nucleotide, Scavenger Receptors, Class B/blood",

author = "Markus Scholz and Katrin Horn and Janne Pott and Arnd Gross and Kleber, {Marcus E} and Delgado, {Graciela E} and Mishra, {Pashupati Prasad} and Holger Kirsten and Christian Gieger and Martina M{\"u}ller-Nurasyid and Anke T{\"o}njes and Peter Kovacs and Terho Lehtim{\"a}ki and Olli Raitakari and Mika K{\"a}h{\"o}nen and Helena Gylling and Ronny Baber and Berend Isermann and Michael Stumvoll and Markus Loeffler and Winfried M{\"a}rz and Thomas Meitinger and Annette Peters and Joachim Thiery and Daniel Teupser and Uta Ceglarek",

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doi = "10.1038/s41467-021-27706-6",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Scholz, M, Horn, K, Pott, J, Gross, A, Kleber, ME, Delgado, GE, Mishra, PP, Kirsten, H, Gieger, C, Müller-Nurasyid, M, Tönjes, A, Kovacs, P, Lehtimäki, T, Raitakari, O, Kähönen, M, Gylling, H, Baber, R, Isermann, B, Stumvoll, M, Loeffler, M, März, W, Meitinger, T, Peters, A, Thiery, J, Teupser, D & Ceglarek, U 2022, 'Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis', Nature Communications, vol. 13, 143. https://doi.org/10.1038/s41467-021-27706-6

TY - JOUR

T1 - Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

AU - Scholz, Markus

AU - Horn, Katrin

AU - Pott, Janne

AU - Gross, Arnd

AU - Kleber, Marcus E

AU - Delgado, Graciela E

AU - Mishra, Pashupati Prasad

AU - Kirsten, Holger

AU - Gieger, Christian

AU - Müller-Nurasyid, Martina

AU - Tönjes, Anke

AU - Kovacs, Peter

AU - Lehtimäki, Terho

AU - Raitakari, Olli

AU - Kähönen, Mika

AU - Gylling, Helena

AU - Baber, Ronny

AU - Isermann, Berend

AU - Stumvoll, Michael

AU - Loeffler, Markus

AU - März, Winfried

AU - Meitinger, Thomas

AU - Peters, Annette

AU - Thiery, Joachim

AU - Teupser, Daniel

AU - Ceglarek, Uta

PY - 2022/1/10

Y1 - 2022/1/10

N2 - Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.

AB - Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.

KW - ABO Blood-Group System/blood

KW - ATP Binding Cassette Transporter, Subfamily G, Member 5/blood

KW - ATP Binding Cassette Transporter, Subfamily G, Member 8/blood

KW - Adult

KW - Apolipoproteins E/blood

KW - Cholesterol/blood

KW - Coronary Artery Disease/blood

KW - Female

KW - Gene Expression Regulation

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Hydroxymethylglutaryl CoA Reductases/blood

KW - Lipase/blood

KW - Lipid Metabolism/genetics

KW - Lipoproteins/blood

KW - Male

KW - Membrane Transport Proteins/blood

KW - Mendelian Randomization Analysis

KW - Multifactorial Inheritance

KW - Phytosterols/blood

KW - Polymorphism, Single Nucleotide

KW - Scavenger Receptors, Class B/blood

U2 - 10.1038/s41467-021-27706-6

DO - 10.1038/s41467-021-27706-6

M3 - Article

C2 - 35013273

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 143

ER -

Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Abstract

Keywords

Publication forum classification

UN SDGs

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