Association of circulating transcriptomic profiles with mortality in sickle cell disease

Abstract

• We validated the association of a circulating genome-wide gene expression profile with poor outcomes in 3 cohorts of SCD.• A composite risk score using this genomic biomarker with clinical risk factors exhibited improved prediction than clinical factors alone.Sickle cell disease (SCD) complications are associated with increased morbidity and risk of mortality. We sought to identify a circulating transcriptomic profile predictive of these poor outcomes in SCD. Training and testing cohorts consisting of adult patients with SCD were recruited and prospectively followed. A pathway-based signature derived from grouping peripheral blood mononuclear cell transcriptomes distinguished 2 patient clusters with differences in survival in the training cohort. These findings were validated in a testing cohort in which the association between cluster 1 molecular profiling and mortality remained significant in a fully adjusted model. In a third cohort of West African children with SCD, cluster 1 differentiated SCD severity using a published scoring index. Finally, a risk score composed of assigning weights to cluster 1 profiling, along with established clinical risk factors using tricuspid regurgitation velocity, white blood cell count, history of acute chest syndrome, and hemoglobin levels, demonstrated a higher hazard ratio for mortality in both the training and testing cohorts compared with clinical risk factors or cluster 1 data alone. Circulating transcriptomic profiles are a powerful method to risk-stratify severity of disease and poor outcomes in both children and adults, respectively, with SCD and highlight potential associated molecular pathways. (Blood. 2017;129(22):3009-3016)

Genetic modifiers of long‐term survival in sickle cell anemia

“…To this end, we queried the significant pathways identified by sequence analysis in the present study against the most differentially dysregulated pathways in the two largest studies of global gene expression profiles in relation to SCD severity. 22 Our findings show that most of our significant pathways also show significant transcriptomic differences in relation to SCD severity (Table 4), thus providing supportive evidence that these pathways are important in SCD pathophysiology.…”

“…For the extreme contrast of "stroke" versus "long survivor", only four gene sets -SERPINC1, SLC22A5, CACNA1H, and SLC4A1 [MIM: 109270] -were significant. Notably, these TA B L E 4 Significant pathways in this study that are also significant in global transcriptomic studies of SCD 21,22 four genes were not significant in the stroke association or long survival association tests, indicating that additional information was gained from this comparison. The significant gene sets in the rare variant association analyses included most of the genes found to harbor recurrent deleterious variants in both the discovery and replication cohort (Table 2) and/or showing unusual allele frequency distributions (Table S4).…”

“…Transcriptomic expression of complement and coagulation components in circulation was increased in a cluster of African American SCD patients with higher severity and mortality rate. 21,22 Moreover, there is evidence of increased complement activation in older patients with SCD, 31 and a complement gene C5 mutation was associated with stroke in SCD patients. 13 In summary, the evidence from this and other studies suggest that long survival is characterized by mutations that confer protection for adverse phenotypes (notably stroke) given that these genes influence intermediate phenotypes for stroke (including blood pressure and endothelial function) while the overt stroke phenotype in SCA is associated with mutations in genes that are involved in the complement and coagulation cascade.…”

Measuring success: utility of biomarkers in sickle cell disease clinical trials and care

“…A composite risk score developed by combining established clinical risk factors along with circulating blood mononuclear transcriptomes has been shown to be predictive of mortality in 2 prospective cohorts of adults with SCD compared with either clinical risk factors or gene expression profiling alone. 133 Similarly, Du et al used cluster analysis to test the signatures of 17 biomarkers with various clinical complications in the CSSCD cohort and correlated them with markers of pulmonary vascular disease in 2 recent pulmonary hypertension clinical trials in children and adults with SCD. 134 Conclusions SCD is a heterogeneous disorder with a wide range of clinical complications and chronic end-organ damage.…”

A common molecular signature of patients with sickle cell disease revealed by microarray meta-analysis and a genome-wide association study

“…Several technologies [ 7 , 8 ] have been developed to identify candidate markers and have highlighted potential molecular pathways related to SCD. Among the high-throughput genomic technologies that have contributed to the identification of candidate genes and to our understanding of complex interactions in multisystem diseases is the microarray technology.…”