Proteogenomic analysis in sickle cell disease identifies 560 pQTL and prioritizes five proteins for HbF investigation

This observational proteogenomic analysis measured 5,411 plasma proteins in 343 sickle cell disease (SCD) patients to identify protein quantitative trait loci (pQTL) associated with common genetic variation. The study compared pQTL effect sizes to those in non-SCD African American individuals from the Million Veteran Program. The primary outcome was the identification of pQTL associated with plasma protein levels.

After conditional analyses, the study identified 560 pQTL, of which 58 (approximately 10%) were novel. The effect sizes of these pQTL were reported to be largely concordant between the SCD cohort and the non-SCD controls. However, evidence of heterogeneity in pQTL effect was noted for two specific proteins: APOL1 and haptoglobin. Using Mendelian randomization, the analysis prioritized five proteins—ENPP5, LBP, NAAA, PT3X, and ZP3—as potentially increasing fetal hemoglobin (HbF) production.

Safety and tolerability data were not reported. Key limitations include the observational nature of the analysis, which establishes association, not causation. The clinical relevance of the pQTL associations in non-SCD individuals was not quantified, and specific effect sizes for the pQTL were not numerically reported. The practice relevance is currently limited, as the findings represent a prioritization of proteins for further functional investigation rather than a direct therapeutic implication.