Elevated plasma complement components in facioscapulohumeral dystrophy

Abstract

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to several therapeutic approaches entering clinical trials and an increased need to develop biomarkers of disease activity and progression. Multiple prior studies have shown early elevation of RNAs encoding components of the complement pathways and relatively widespread activated complement complexes by immunodetection in FSHD muscle. The current study tested plasma from two independent cohorts of FSHD and control subjects and found elevated complement components in both FSHD cohorts. Combining subjects from both cohorts identified complement factors that best distinguished FSHD and controls. Within the FSHD group, a subset of subjects showed elevation in multiple complement components. Together these findings suggest the need for future studies to determine whether measurements of complement activation can be used as a non-invasive measurement of FSHD disease activity, progression and/or response to therapies. In addition, with the ongoing expansion of complement therapeutic approaches, consideration for precision-based targeting of this pathway is appropriate.

Figure 1

Complement cascade system. Diagram showing the complement components of the classical, alternative and terminal pathways of the complement system.

Figure 2

Complement profile in first and second cohorts. (a and b) First cohort complement profiles. (a) Complement level t-tests comparing FSHD and control samples. The horizontal bar depicts the scaled P-value and sign of t-statistics. Orange indicates P-value < 0.05. (b) Violin plots showing the distribution of the complement levels in FSHD and controls. Green and blue dots represent the control and FSHD samples, respectively; red dots are the mean values in each group. (c and d) Complement profiles in the second cohort. (c) Complement level t-tests comparing FSHD and control samples. The horizontal bar depicts the scaled P-value and sign of t-statistics. Orange indicates P-value < 0.05. (d) Violin plots showing the distribution of the complement levels in FSHD and controls. Green and blue dots represent the control and FSHD samples, respectively; red dots are the mean values in each group.

Figure 3

Complement levels and per-sample composite scores of the combined plasma samples from two cohorts. The combined samples include 20 s plasma samples from the first cohort and 41 first plasma samples from the second cohort. (a) A violin plot showing the distribution of the selected complement components in FSHD and controls. Green and blue dots represent the control and FSHD samples, respectively; red dots are the mean values in each group. **P-value < 0.005; P-values of Factor D and sC5b-9 are 0.15 and 0.67, respectively. (b) Hierarchical cluster-based heatmap of the complement levels. The top 17 samples enclosed in the rectangle are FSHD subjects displaying elevation in one or more pathways. (c-d) Waterfall plot (c) and boxplot (d) of per-sample composite z-score, based on the panel of four components (C3, C4b, Factor D and SC5b-9), showing the relative levels of the combined z-score for each subject.