1. Academic Validation
  2. Glucosylsphingosine is a key biomarker of Gaucher disease

Glucosylsphingosine is a key biomarker of Gaucher disease

  • Am J Hematol. 2016 Nov;91(11):1082-1089. doi: 10.1002/ajh.24491.
Vagishwari Murugesan 1 Wei-Lien Chuang 2 Jun Liu 1 Andrew Lischuk 3 Katherine Kacena 4 Haiqun Lin 5 Gregory M Pastores 6 Ruhua Yang 1 Joan Keutzer 2 Kate Zhang 2 Pramod K Mistry 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
  • 2 Sanofi Genzyme, Framingham, Massachusetts.
  • 3 Department of Radiology, Yale University School of Medicine, New Haven, Connecticut.
  • 4 Kacena Consulting, Natick, Massachusetts.
  • 5 Department of Biostatistics, Yale School of Public Health.
  • 6 Department of Neurology, New York University School of Medicine, New York.
  • 7 Department of Internal Medicine & Pediatrics, Yale University School of Medicine, New Haven, Connecticut. pramod.mistry@yale.Edu.
Abstract

Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3-1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4-216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2-129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r = 0.59 P < 0.001), CCL18 (r = 0.62 P <0.001), hepatomegaly (r = 0.28 P < 0.001), splenomegaly (r = 0.27 P = 0.003), splenectomy (P = 0.01) and treatment mode (P < 0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (P < 0.001), splenectomy (P = 0.02), Chitotriosidase (P < 0.001) and CCL18 levels (P = 0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136-90.3 ng/ml P < 0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT. Am. J. Hematol. 91:1082-1089, 2016. © 2016 Wiley Periodicals, Inc.

Figures
Products