Associations between SNPs in Intestinal Cholesterol Absorption and Endogenous Cholesterol Synthesis Genes with Cholesterol Metabolism.

Maite M Schroor,Jogchum Plat,Ronald P Mensink,Fatma B A Mokhtar

doi:10.3390/biomedicines9101475

Maite M Schroor, Jogchum Plat + Show 2 more

Open Access

https://doi.org/10.3390/biomedicines9101475

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Journal: Biomedicines	Publication Date: Oct 14, 2021
Citations: 12	License type: CC BY 4.0

Affiliation: Maastricht University

Abstract

Single nucleotide polymorphisms (SNPs) have been associated with cholesterol metabolism and may partly explain large inter-individual variability in intestinal cholesterol absorption and endogenous cholesterol synthesis rates. This cross-sectional study therefore examined whether SNPs in genes encoding for proteins involved in intestinal cholesterol absorption (ABCG5, ABCG8, and NPC1L1) and endogenous cholesterol synthesis (CYP51A1, DHCR7, DHCR24, HMGCR, HSD17B7, LBR, and MSMO1) were associated with intestinal cholesterol absorption markers (total cholesterol (TC) standardized campesterol and sitosterol levels), an endogenous cholesterol synthesis marker (TC-standardized lathosterol levels), and serum low-density lipoprotein cholesterol (LDL-C) concentrations in a European cohort. ABCG5 (rs4245786) and the tag SNP ABCG8 (rs4245791) were significantly associated with serum campesterol and/or sitosterol levels. In contrast, NPC1L1 (rs217429 and rs217416) were significantly associated with serum lathosterol levels. The tag SNP in HMGCR (rs12916) and a SNP in LBR (rs12141732) were significantly associated with serum LDL-C concentrations. SNPs in the cholesterol absorption genes were not associated with serum LDL-C concentrations. SNPs in CYP51A1, DHCR24, HSD17B7, and MSMO1 were not associated with the serum non-cholesterol sterols and LDL-C concentrations. Given the variable efficiency of cholesterol-lowering interventions, the identification of SNPs associated with cholesterol metabolism could be a step forward towards personalized approaches.

Highlights

Cholesterol homeostasis is determined by the interaction between various complex processes including intestinal dietary and biliary cholesterol absorption, and endogenous cholesterol synthesis [1,2]
Concentrations terol was positively associated with campesterol (β = 1.39 × 102 μmol/mmol TC; p < 0.001)
We found that SNPs in ABCG5 and ABCG8 were associated with intestinal cholesterol absorption, while SNPs in Niemann-Pick C1-Like 1 (NPC1L1) were significantly associated with endogenous cholesterol synthesis

Summary

Introduction

Cholesterol homeostasis is determined by the interaction between various complex processes including intestinal dietary and biliary cholesterol absorption, and endogenous cholesterol synthesis [1,2]. De novo cholesterol synthesis, which involves approximately 30 reactions and more than 20 different enzymes, mainly takes place in the liver [2]. The endogenous cholesterol synthesis pathway starts with acetyl-CoA, which is converted into the intermediate lanosterol in a multistep process. Lanosterol is converted into cholesterol via either the Bloch or the Kandutsch–Russell pathway (Figure S2). The intermediates in these two pathways differ, but the same enzymes are involved [5,6,7,8].

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