title: Glucosylsphingosine is a key biomarker of Gaucher disease.
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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Vagishwari
authors.initials: V
authors.lastname: Murugesan
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Chuang
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lischuk
authors.affiliation: Kacena Consulting, Natick, Massachusetts.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kacena
authors.affiliation: Department of Biostatistics, Yale School of Public Health.
authors.forename: Haiqun
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Neurology, New York University School of Medicine, New York.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Ruhua
authors.initials: R
authors.lastname: Yang
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts.
authors.forename: Joan
authors.initials: J
authors.lastname: Keutzer
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts.
authors.forename: Kate
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine & Pediatrics, Yale University School of Medicine, New Haven, Connecticut. pramod.mistry@yale.Edu.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D005260:Female; D005776:Gaucher Disease / Q000097:blood* / Q000188:drug therapy / Q000628:therapy; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D011609:Psychosine / Q000031:analogs & derivatives* / Q000097:blood; D011759:Pyrrolidines / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011759:Pyrrolidines; D011609:Psychosine; C035742:sphingosyl beta-glucoside; C522917:eliglustat