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 and Uta Ceglarek
Additional contact information
Markus Scholz: University of Leipzig
Katrin Horn: University of Leipzig
Janne Pott: University of Leipzig
Arnd Gross: University of Leipzig
Marcus E. Kleber: Heidelberg University
Graciela E. Delgado: Heidelberg University
Pashupati Prasad Mishra: Tampere University
Holger Kirsten: University of Leipzig
Christian Gieger: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Martina Müller-Nurasyid: Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
Anke Tönjes: University Hospital Leipzig
Peter Kovacs: German Center for Diabetes Research (DZD)
Terho Lehtimäki: Tampere University
Olli Raitakari: Tampere University
Mika Kähönen: Tampere University
Helena Gylling: University of Helsinki and Helsinki University Hospital
Ronny Baber: University of Leipzig
Berend Isermann: University Hospital Leipzig
Michael Stumvoll: University Hospital Leipzig
Markus Loeffler: University of Leipzig
Winfried März: Heidelberg University
Thomas Meitinger: Technical University of Munich
Annette Peters: Institue of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Joachim Thiery: University of Leipzig
Daniel Teupser: Ludwig-Maximilians University of Munich
Uta Ceglarek: University of Leipzig

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27706-6

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