Evaluation of potential serum biomarkers for individuals at risk of multiple sclerosis highlights SPP1.

Circulating proteins have been widely investigated as potential biomarkers in multiple sclerosis (MS), yet findings across studies are often inconsistent, likely reflecting differences in disease stage, treatment exposure, and cohort composition. Studying individuals at elevated risk of MS prior to disease onset offers a unique opportunity to identify immune alterations that precede clinical disease while minimizing confounders. Here, we investigated whether alterations in six previously MS-associated biomarkers are detectable and associated with underlying genetic susceptibility in two independent sample collections consisting of persons with MS (pwMS), healthy participants, and asymptomatic first-degree relatives of pwMS from the Genes & Environment in MS (GEMS) study cohort. The panel, representing complementary axes of MS immunopathology, included granzyme A (GZMA), MER tyrosine kinase (MERTK), interleukin-2 receptor alpha (IL2RA), osteopontin (SPP1), CD30 (TNFRSF8), and chitinase-3-like protein 1 (CHI3L1). None of the proteins demonstrated associations with MS. A composite score constructed from externally derived effect estimates was associated with neither MS nor first-degree-relative status. Among asymptomatic first-degree relatives, higher genetic risk was associated with lower SPP1 levels for both the overall MS GRS and its non-MHC component, while TNFRSF8 was inversely associated with the non-MHC GRS in secondary analyses. Together, these findings suggest that several circulating proteins recently proposed as MS biomarkers are not robust tools to distinguish MS from healthy individuals. However, SPP1 levels are highlighted for further evaluation among at-risk individuals to determine whether circulating immune signatures can capture the earliest stages of MS in at-risk individuals.