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.

Figure 1

(A and B) Median and mean values of Lyso-GL1 in cohort 1—Before ERT & after ERT against healthy controls. The levels of circulating Lyso GL1 values were assessed in treatment naïve patients before ERT & after ERT and compared against health controls (n = 41). In Panel A, values are expressed as median (horizontal line in each box), 25th and 75th centiles (top and bottom lines of the box) and 10th and 90th centiles (top and bottom of each whisker). In panel B, distribution of Lyso GL1 measurements across untreated, treated and healthy controls is shown. Mean values are marked by a x. There was barely detectable level of Lyso-GL1 in plasma of healthy controls (1.5 ng/ml; 1.3–1.7 95% CI). At baseline prior to initiation of imiglucerase ERT, average lyso-GL1 levels were 180.9 ng/ml (145.4–216.5; 95% CI) and decreased to a mean of 89 ng/ml (69.2–129.4; 95% CI) after therapy. (C) Trend in Chitotriosidase against Lyso-GL1 over 5 years of ERT Treatment. N = 25 (Year 1); N = 20 (Year 2); N = 5 (Year 3); N = 7 (Year 4); N = 3 (Year 5). The biomarker elevation in patients were averaged from year one to year five and divided by the upper limit of normal (ULN) taken as 125 nm/ml/h for chitotriosidase and 2.7 ng/ml for Lyso-GL1. The average fold elevation of each biomarker per year is graphed. Lyso-GL1 was correlated with visceral and serum markers of Gaucher disease burden to assess its utility as a biomarker. Non-normally distributed data was logarithmically transformed and correlated using Pearson's correlation coefficient. (D) Lyso-GL1 correlation with Chitotriosidase (r = 0.59 P < 0.001 n = 209) (E) Lyso- GL1 correlation with CCL 18 (r = 0.62 P < 0.001 n = 252) (H) Lyso-GL1 correlation with liver volume as multiples of normal (r = 0.28 P < 0.001 n = 150) (I) Lyso-GL1 correlation with spleen volume as multiples of normal (r = 0.27 P = 0.003 n = 115) (F) Lyso GL1 correlation with age in years (r = −0.22 P < 0.001) G. Lyso-GL1 levels between patients with intact spleens and splenectomy (P = 0.01) J. Lyso-GL1 levels between patients on ERT and SRT (P < 0.001).

Figure 2

Propensity Score Matching between ERT and ELI-SRT patients. Top panel: Comparison of Propensity scores between the ERT and SRT cohort of patients. Table shows baseline Characteristics of unmatched and matched patients receiving ERT and SRT.