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Regenerating Islet-Derived 3α Is a Predictive Biomarker of Complicated Disease From Preclinical Through Established
Jennifer D Claytor1, Anna-Teresa D'Hooghe2, Arno R Bourgonje3
1The Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; Jill Roberts Center for Inflammatory Bowel Disease Research, Weill Cornell Medicine-New York Presbyterian Hospital, New York, New York.
Background & Aims:
Regenerating islet-derived 3α (REG3α) is a serum biomarker in patients with graft-vs-host disease linked to 6-month mortality. REG3α is produced by intestinal Paneth cells, which are implicated in Crohn's disease (CD) pathophysiology. The aim of this study was to assess associations between serum REG3α and progressive CD.
Methods:
Serum REG3α was measured in 2 cross-sectional (Mount Sinai, Leuven) and a prediagnostic cohort (PREDICTS) with serial samples up to 10 years before CD diagnosis. Tissue REG3α expression was assessed via bulk RNA sequencing from paired ileal and colonic biopsies. Serum REG3α and tissue REG3α were associated with CD progression (hospitalization, surgery, steroid course, or new advanced therapy). Single-cell RNA sequencing data explored associations between REG3α expression, Paneth cell phenotypes, and CD.
Results:
In 394 patients, high serum REG3α was associated with CD progression, independent of C-reactive protein and endoscopic activity (Mt Sinai: hazard ratio [HR], 1.9; (95% confidence interval [CI], 1.3-2.8; Leuven: HR, 2.9; 95% CI, 1.9-4.6; both P < .001). The association persisted in patients with mild or inactive CD. In the prediagnostic cohort, high serum REG3α predicted the development of CD, particularly complicated (B2/3) and surgical presentations, up to 10 years before diagnosis (P). Analysis of REG3α expression and Paneth cell transcriptomes suggested that CD is associated with loss of regenerative Paneth cell populations and enrichment in REG3α-expressing populations, suggesting a mechanism through which changes in serum REG3α associate with complicated CD.
Conclusions:
Serum REG3α holds potential as a noninvasive, prognostic biomarker in CD, independent of disease activity. High serum REG3α, even years before diagnosis, is linked to a complicated disease course.
