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

• Published in: Nature communications Vol. 13; no. 1; pp. 143 - 12
• Main Authors: Scholz, Markus, Horn, Katrin, Pott, Janne, Gross, Arnd, Kleber, Marcus E., Delgado, Graciela E., Mishra, Pashupati Prasad, Kirsten, Holger, Gieger, Christian, Müller-Nurasyid, Martina, Tönjes, Anke, Kovacs, Peter, Lehtimäki, Terho, Raitakari, Olli, Kähönen, Mika, Gylling, Helena, Baber, Ronny, Isermann, Berend, Stumvoll, Michael, Loeffler, Markus, März, Winfried, Meitinger, Thomas, Peters, Annette, Thiery, Joachim, Teupser, Daniel, Ceglarek, Uta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 631/208/205/2138; 692/308/2056; 692/4017; 692/699/75; ABO Blood-Group System - blood; ABO Blood-Group System - genetics; Adult; Apolipoprotein E; Apolipoproteins E - blood; Apolipoproteins E - genetics; Arteriosclerosis; Atherosclerosis; ATP Binding Cassette Transporter, Subfamily G, Member 5 - blood; ATP Binding Cassette Transporter, Subfamily G, Member 5 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 8 - blood; ATP Binding Cassette Transporter, Subfamily G, Member 8 - genetics; Cardiovascular disease; Cholesterol; Cholesterol - blood; Coronary artery; Coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - genetics; Coronary Artery Disease - pathology; Coronary vessels; Esterification; Female; Gene Expression Regulation; Gene loci; Genetic control; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Heart diseases; Heterogeneity; Homology; Humanities and Social Sciences; Humans; Hydroxymethylglutaryl CoA Reductases - blood; Hydroxymethylglutaryl CoA Reductases - genetics; Lipase - blood; Lipase - genetics; Lipid Metabolism - genetics; Lipoproteins - blood; Lipoproteins - genetics; Male; Membrane Transport Proteins - blood; Membrane Transport Proteins - genetics; Mendelian Randomization Analysis; Meta-analysis; multidisciplinary; Multifactorial Inheritance; Phytosterols; Phytosterols - blood; Polygenic inheritance; Polymorphism, Single Nucleotide; Scavenger Receptors, Class B - blood; Scavenger Receptors, Class B - genetics; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Vein & artery diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27706-6

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.