02884nas a2200289 4500000000100000008004100001260001600042100001600058700001700074700002100091700001000112700001100122700001500133700001300148700001200161700001600173700001100189700001600200700001700216700001200233245007800245856007500323300001100398490000700409520216400416022001402580 2021 d bElsevier BV 1 aTió-Coma M 1 aKiełbasa SM 1 avan den Eeden SJ 1 aMei H 1 aRoy JC 1 aWallinga J 1 aKhatun M 1 aSoren S 1 aChowdhury A 1 aAlam K 1 avan Hooij A 1 aRichardus JH 1 aGeluk A 00 aBlood RNA signature RISK4LEP predicts leprosy years before clinical onset uhttps://www.thelancet.com/action/showPdf?pii=S2352-3964%2821%2900172-9 a103379 0 v68 3 aBackground
Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is often late- or misdiagnosed leading to irreversible disabilities. Blood transcriptomic biomarkers that prospectively predict those who progress to leprosy (progressors) would allow early diagnosis, better treatment outcomes and facilitate interventions aimed at stopping bacterial transmission. To identify potential risk signatures of leprosy, we collected whole blood of household contacts (HC, n=5,352) of leprosy patients, including individuals who were diagnosed with leprosy 4-61 months after sample collection.
Methods
We investigated differential gene expression (DGE) by RNA-Seq between progressors before presence of symptoms (n=40) and HC (n=40), as well as longitudinal DGE within each progressor. A prospective leprosy signature was identified using a machine learning approach (Random Forest) and validated using reverse transcription quantitative PCR (RT-qPCR).
Findings
Although no significant intra-individual longitudinal variation within leprosy progressors was identified, 1,613 genes were differentially expressed in progressors before diagnosis compared to HC. We identified a 13-gene prospective risk signature with an Area Under the Curve (AUC) of 95.2%. Validation of this RNA-Seq signature in an additional set of progressors (n=43) and HC (n=43) by RT-qPCR, resulted in a final 4-gene signature, designated RISK4LEP (MT-ND2, REX1BD, TPGS1, UBC) (AUC=86.4%).
Interpretation
This study identifies for the first time a prospective transcriptional risk signature in blood predicting development of leprosy 4 to 61 months before clinical diagnosis. Assessment of this signature in contacts of leprosy patients can function as an adjunct diagnostic tool to target implementation of interventions to restrain leprosy development.
Funding
This study was supported by R2STOP Research grant, the Order of Malta-Grants-for-Leprosy-Research, the Q.M. Gastmann-Wichers Foundation and the Leprosy Research Initiative (LRI) together with the Turing Foundation (ILEP# 702.02.73 and # 703.15.07). a2352-3964