Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE.

George A Robinson,Meena Naja,Elizabeth C Jury,Leda Coelewij,Kirsty E Waddington,David A Isenberg,Ines Pineda-Torra,Hannah Peckham,Anna Radziszewska,Junjie Peng,Coziana Ciurtin,Yiannis Ioannou,Chris Wincup

doi:10.1016/j.ebiom.2021.103243

Abstract

BackgroundCardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE.MethodsSerum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples.FindingsHierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up.InterpretationMulti-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes.FundingLupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis.

Highlights

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterised by loss of immune cell regulation, chronic inflammation and multiple organ damage
Group-1 was characterised by reduced serum high-density lipoprotein (HDL) and elevated very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles suggestive of an atherogenic metabolomic profile; Group-2 had elevated HDL and reduced VLDL/IDL/LDL particles À a more atheroprotective profile and; Group-3 had relatively low serum levels of HDL and VLDL/LDL/IDL particles (Fig. 1a and b, Supplementary Table 2)
The results suggest that ApoB:ApoA1 ratio could be a robust biomarker for prediction of increased cardiovascular disease (CVD) risk in patients with juvenile-onset systemic lupus erythematosus (JSLE), even in patients with relatively low disease activity

Summary

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterised by loss of immune cell regulation, chronic inflammation and multiple organ damage. Patients with juvenile onset systemic lupus erythematosus (JSLE) have an accelerated risk of developing atherosclerosis, and cardiovascular disease (CVD) is a leading cause of mortality for patients. Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively.

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