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

Nat Commun. 2022 Jan 10;13(1):143. doi: 10.1038/s41467-021-27706-6.

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ABO Blood-Group System / blood
  • ABO Blood-Group System / genetics
  • 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
  • Adult
  • Apolipoproteins E / blood
  • Apolipoproteins E / genetics
  • Cholesterol / blood*
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / pathology
  • Female
  • Gene Expression Regulation
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • 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
  • Multifactorial Inheritance
  • Phytosterols / blood*
  • Polymorphism, Single Nucleotide
  • Scavenger Receptors, Class B / blood
  • Scavenger Receptors, Class B / genetics

Substances

  • ABCG5 protein, human
  • ABCG8 protein, human
  • ABO Blood-Group System
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ApoE protein, human
  • Apolipoproteins E
  • Lipoproteins
  • Membrane Transport Proteins
  • NPC1L1 protein, human
  • Phytosterols
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • Cholesterol
  • HMGCR protein, human
  • Hydroxymethylglutaryl CoA Reductases
  • Lipase
  • PNLIP protein, human