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.

Physterols are cholesterol homologs derived from plants, which are found in humans through consumption of plant products. Here the authors have performed a genome-wide meta-analysis of 32 serum phytosterol traits, with evidence suggesting causality between sitosterol and coronary artery disease.

Details

Title
Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis
Author
Scholz, Markus 1   VIAFID ORCID Logo  ; Horn, Katrin 1   VIAFID ORCID Logo  ; Pott Janne 1   VIAFID ORCID Logo  ; Gross, Arnd 2   VIAFID ORCID Logo  ; Kleber, Marcus E 3   VIAFID ORCID Logo  ; Delgado, Graciela E 3 ; Mishra Pashupati Prasad 4   VIAFID ORCID Logo  ; Kirsten, Holger 1   VIAFID ORCID Logo  ; Gieger, Christian 5   VIAFID ORCID Logo  ; Müller-Nurasyid Martina 6 ; Tönjes Anke 7 ; Kovacs, Peter 8   VIAFID ORCID Logo  ; Lehtimäki Terho 4   VIAFID ORCID Logo  ; Raitakari Olli 9 ; Kähönen Mika 9 ; Gylling Helena 10 ; Baber Ronny 11 ; Isermann Berend 12 ; Stumvoll, Michael 7   VIAFID ORCID Logo  ; Loeffler, Markus 1 ; März Winfried 13 ; Meitinger, Thomas 14 ; Peters, Annette 15   VIAFID ORCID Logo  ; Thiery Joachim 11 ; Teupser, Daniel 16 ; Ceglarek Uta 11 

1  University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786); University of Leipzig, LIFE Research Center for Civilization Diseases, Medical Faculty, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
2  University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786) 
3  Heidelberg University, Medical Faculty Mannheim, Vth Department of Medicine, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
4  Tampere University, Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
5  Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); German Center for Diabetes Research (DZD), Munich, Germany (GRID:grid.452622.5) 
6  Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Ludwig-Maximilians University of Munich, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X); University Medical Center, Johannes Gutenberg University, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Mainz, Germany (GRID:grid.410607.4); Hospital of the Ludwig-Maximilians-University Munich, Department of Internal Medicine I (Cardiology), Munich, Germany (GRID:grid.411095.8) (ISNI:0000 0004 0477 2585) 
7  University Hospital Leipzig, Medical Department III – Endocrinology, Nephrology, Rheumatology, Leipzig, Germany (GRID:grid.411339.d) (ISNI:0000 0000 8517 9062) 
8  German Center for Diabetes Research (DZD), Munich, Germany (GRID:grid.452622.5); University Hospital Leipzig, Medical Department III – Endocrinology, Nephrology, Rheumatology, Leipzig, Germany (GRID:grid.411339.d) (ISNI:0000 0000 8517 9062) 
9  Tampere University, Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
10  University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Cardiology, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
11  University of Leipzig, LIFE Research Center for Civilization Diseases, Medical Faculty, Leipzig, Germany (GRID:grid.9647.c) (ISNI:0000 0004 7669 9786); University Hospital Leipzig, Institute for Laboratory Medicine Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany (GRID:grid.411339.d) (ISNI:0000 0000 8517 9062) 
12  University Hospital Leipzig, Institute for Laboratory Medicine Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany (GRID:grid.411339.d) (ISNI:0000 0000 8517 9062) 
13  Heidelberg University, Medical Faculty Mannheim, Vth Department of Medicine, Heidelberg, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373); Synlab Academy, Synlab Holding Deutschland GmbH, Augsburg, Germany (GRID:grid.461810.a) (ISNI:0000 0004 0572 0285); Medical University Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria (GRID:grid.11598.34) (ISNI:0000 0000 8988 2476) 
14  Technical University of Munich, Institue for Human Genetics, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
15  Institue of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
16  Ludwig-Maximilians University of Munich, Insitute for Laboratory Medicine, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-27706-6
ProQuest document ID
2619581291
Copyright
© The Author(s) 2022. corrected publication 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.