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

Abstract

Background Cardiovascular 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. Methods Serum 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. Findings Hierarchical 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. Interpretation Multi-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. Funding Lupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis.

Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood

“…In that study, ApoB and ApoA1 were stronger predictors of abnormal vascular changes than conventional cholesterol measurements (LDL-C and HDL-C), which suggests that the carriers (apolipoproteins) might play a more central role than the actual lipid content transported in these lipoprotein particles. These findings are further supported by the Pathobiological Determinants of Atherosclerosis in Youth study which found apolipoproteins associated with post-mortem arterial lesions, [19] and the Bogalusa Heart Study, which showed that high ApoB/ApoA1 ratio in children was associated with incidence of parental myocardial infarction, [20] and a recent publication identifying ApoB/ApoA ratio as a predictor of cardiovascular risk in adolescent SLE patients [21] . A recent study also showed that increased ApoB/ApoA1 ratio predicts cardiometabolic risk in patients with juvenile onset systemic lupus erythematosus [21] .…”

“…These findings are further supported by the Pathobiological Determinants of Atherosclerosis in Youth study which found apolipoproteins associated with post-mortem arterial lesions, [19] and the Bogalusa Heart Study, which showed that high ApoB/ApoA1 ratio in children was associated with incidence of parental myocardial infarction, [20] and a recent publication identifying ApoB/ApoA ratio as a predictor of cardiovascular risk in adolescent SLE patients [21] . A recent study also showed that increased ApoB/ApoA1 ratio predicts cardiometabolic risk in patients with juvenile onset systemic lupus erythematosus [21] .…”

Biomarkers Associated with Organ-Specific Involvement in Juvenile Systemic Lupus Erythematosus

“…Evidence suggests that lipoprotein biomarkers could be used predict atherosclerotic risk in adults with SLE [ 146 , 147 ]. A study using in-depth metabolomics by Robinson et al identified that the ApoB:ApoA1 ratio was a strong biomarker of CVD in JSLE, independent of clinical disease measures and body mass index (BMI) [ 118 ]. This finding has been validated in 2 separate cohorts using ultrasound evidence for the presence of subclinical atherosclerotic plaque in adult SLE patients [ 146 ].…”

How to predict the prognosis in juvenile-onset SLE?

“…In this issue of EBioMedicine, Robinson and co-workers identified a novel risk marker, apolipoprotein B (apoB)-to-apoA1 ratio, from an investigation integrating metabolomics, transcriptome, immune profiles, and clinical data of patients with JSLE. They verified its usefulness by conducting longterm observational clinical cohort studies and comparing clinical information between adult patients with SLE and mouse atherosclerotic models [4].ApoB and apoA1 are major apolipoproteins involved in lipid transport and the pathogenic processes and complications of atherosclerosis. These are the major protein components in very-low-, intermediate-, and low-density lipoproteins, with one protein per particle, and in high-density lipoprotein particles, respectively [5].…”

“…In this issue of EBioMedicine, Robinson and co-workers identified a novel risk marker, apolipoprotein B (apoB)-to-apoA1 ratio, from an investigation integrating metabolomics, transcriptome, immune profiles, and clinical data of patients with JSLE. They verified its usefulness by conducting longterm observational clinical cohort studies and comparing clinical information between adult patients with SLE and mouse atherosclerotic models [4].…”