Race disparity in blood sphingolipidomics associated with lupus cardiovascular comorbidity

Abstract

Systemic lupus erythematous (SLE) is a chronic multi-organ autoimmune disease. Genetic and environmental factors contribute to disease onset and severity. Sphingolipids are signaling molecules involved in regulating cell functions and have been associated with multiple genetic disease processes. African-Americans are more likely to suffer from SLE morbidity than Whites. The Medical University of South Carolina has banked plasma samples from a well-characterized lupus cohort that includes African-Americans and Whites. This study examined the influence of race on plasma sphingolipid profiles in SLE patients and association of sphingolipid levels with comorbid atherosclerosis and SLE disease activity. Mass spectrometry revealed that healthy African-Americans had higher sphingomyelin levels and lower lactosylcermide levels compared to healthy Whites. SLE patients, irrespective of race, had higher levels of ceramides, and sphingoid bases (sphingosine and dihydrosphingosine) and their phosphates compared to healthy subjects. Compared to African-American controls, African-American SLE patients had higher levels of ceramides, hexosylceramides, sphingosine and dihydrosphingosine 1-phosphate. Compared to White controls, White SLE patients exhibited higher levels of sphingoid bases and their phosphates, but lower ratios of C16:0 ceramide/sphingosine 1-phosphate and C24:1 ceramide/sphingosine 1-phosphate. White SLE patients with atherosclerosis exhibited lower levels of sphingoid bases compared to White SLE patients without atherosclerosis. In contrast, African-American SLE patients with atherosclerosis had higher levels of sphingoid bases and sphingomyelins compared to African-American SLE patients without atherosclerosis. Compared to White SLE patients with atherosclerosis, African-American SLE patients with atherosclerosis had higher levels of select sphingolipids. Plasma levels of sphingosine, C16:0 ceramide/sphingosine 1-phosphate ratio and C24:1 ceramide/sphingosine 1-phosphate ratio significantly correlated with SLEDAI in the African-American but not White SLE patients. The C16:0 ceramide/sphingosine 1-phosphate ratio in SLE patients, and levels of C18:1 and C26:1 lactosylcermides, C20:0 hexosylceramide, and sphingoid bases in SLE patients with atherosclerosis could be dependent on race. Further ethnic studies in SLE cohorts are necessary to verify use of sphingolipidomics as complementary diagnostic tool.

Sphingolipids and Diagnosis, Prognosis, and Organ Damage in Systemic Lupus Erythematosus

“…In the setting of lupus nephritis, it is possible that in the Checa et al (41) study the plasma S1P fraction bound to albumin (22) is depleted due to its excretion with the urine (albuminuria). Patyna et al (53) showed that S1P and dhS1P levels were higher in plasma samples of SLE patients (irrespective of renal function) compared to healthy controls, which is in agreement with data from the Hammad et al (18) study. In the Patyna et al (53) study sphingosine and C16:0, C18:0, C20:0, and C24:1 ceramide levels were elevated only in SLE patients suffering from impaired renal function, compared to healthy controls and SLE patients without impaired renal function.…”

“…Notably, C16:0 ceramide/S1P ratio in SLE patients, and levels of C18:1 and C26:0 Lact-Cer, C20:1 Hex-Cer, and sphingoid bases in SLE patients with atherosclerosis could be dependent on race and indicate that there are race-dependent factors, which may regulate the homeostasis of the sphingolipid metabolic and signaling pathways, including the activity of sphingolipid metabolizing enzymes, which may influence the levels of circulating sphingolipids. As for disease activity, plasma levels of sphingosine, C16:0 ceramide/S1P ratio and C24:1 ceramide/S1P ratio significantly correlated with SLEDAI in the African-American but not White SLE patients (18). Further ethnic studies in SLE cohorts are needed to assess the use of plasma sphingolipidomics as an added diagnostic tool.…”

“…Sphingolipids are typically measured using mass spectroscopy with a triple-quadrupole mass spectrometer alone or with high performance liquid chromatography in tandem with high performance liquid chromatography, which provides more sensitivity and specificity of the analyses. Analytical approaches are either non-targeted (shotgun) lipidomics or targeted lipidomics; both approaches have been adopted in plasma sphingolipidomics analysis in SLE (17,18).…”

“…Furthermore, African-Americans normally have lower triglycerides and higher HDL cholesterol levels than other ethnicities; however, paradoxically they have increased risk of CVD (66). Our group has recently examined the influence of race on plasma sphingolipid profiles in SLE patients and associations of sphingolipid levels with comorbid atherosclerosis and SLE disease activity (18). Compared to healthy Whites, healthy African-Americans had higher SM levels and lower Lact-Cer levels.…”

Transcriptomics Reveal Altered Metabolic and Signaling Pathways in Podocytes Exposed to C16 Ceramide-Enriched Lipoproteins

“…Additionally, SMPD1 and 4 which encode lysosomal acid sphingomyelinase and neutral membrane sphingomyelinase, respectively, were also upregulated. Recent findings strongly support that altered circulating sphingolipids are associated with the development of nephropathy in diabetes [15,45] and lupus [41,46]. How different circulating sphingolipids influence renal sphingolipid metabolism and signaling remains to be investigated.…”