Defining the relationship between lipids and immune traits in TwinsUK
Authors: Christofidou P , Liechti T , Roederer M , Beddall M , Menni C , Spector T , Mangino M 
Published: October 2021

Abstract

Introduction
Lipid metabolism plays a crucial role in both innate and adaptive immune responses. Blood lipids are well known biomarkers of heart disease and atherosclerosis. Given that immune responses are involved in atherosclerosis development and progression, it is of utmost importance to explore the mutual relationship between circulating lipid measures and immunology markers, to better manage cardiovascular disease (CVD).

Purpose
The aim of this work was to evaluate relationships of distinct immune cell subtypes and circulating lipids in a general population setting.

Methods
We investigated the associations between 3,734 immune traits and circulating lipids [LDL-C, HDL-C, total cholesterol (TC), triglycerides (TG), non-HDL-C) in 2,056 individuals from the TwinsUK cohort. Immune traits were defined by high-dimensional flow-cytometry which enabled in-depth assessment of all major lymphocyte and myeloid subsets in peripheral blood. Information on immune cell subset frequency (FREQ) and mean fluorescence intensity (MFI) was available. A linear mixed model regression analysis adjusted for family structure, gender, age and BMI was used to examine the associations between immune traits and lipids. We then undertook a sub-analysis in 608 individuals and 131 lipid metabolites quantified using nuclear magnetic resonance spectroscopy to investigate the associations of specific immune traits and lipoprotein particles.

Results
We observed 18 significant associations (Bonferroni P-value &lt;7.3x10–6) between 9 MFI immune traits and lipids. These involved associations between circulating lipids and 7 different myeloid or lymphoid subsets of immune cells including monocytes and natural killer cells. The top associations were found between CD14+ classical monocytes and non-HDL-C, LDL-C, HDL-C and TG. Increased levels of non-HDL-C (P=4.7x10–14), HDL-C (P=1.9x10–13) and TG (P=8.5x10–10) were associated with lower expression of CD14+ monocytes whereas increased LDL-C was associated with elevated expression of both CD14+ monocytes (P=1.0x10–13) and CD16+CD14+ monocytes (P=2.7x10–8). No significant association was detected between FREQ traits and lipids. We also observed 39 associations (Bonferroni P-value &lt;3.1x10–4) between 19 lipid metabolites and CD14+ classical monocytes. The top associations were linked to different HDL particles (Free cholesterol in L-HDL: P=3.5x10–6; Total cholesterol in L-HDL: P=3.5x10–6; Cholesterol esters in L-HDL: P=4.1x10–6). Different subclasses of VLDL particles were also associated with CD14+ monocytes.

Conclusion
The present study provides the first comprehensive picture of lipid-immune cell associations in the circulatory system. We observed a link between expression levels of CD14+ classical monocytes and circulating lipid metabolites. The same lipid metabolites were previously associated with risk of developing myocardial infarction and stroke speculating a link between CD14+ classical monocytes and CVD risk.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): SYSCID - A Systems medicine approach to chronic inflammatory diseases