{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:02:29Z","timestamp":1777946549335,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,29]]},"group-title":"Immunology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Multiple Sclerosis Society","award":["RG-5003-A-2"],"award-info":[{"award-number":["RG-5003-A-2"]}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences (NCATS), NIH","doi-asserted-by":"crossref","award":["UL1TR001873"],"award-info":[{"award-number":["UL1TR001873"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Intramural Research Program of the National Institutes of Health"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32GM007367"],"award-info":[{"award-number":["T32GM007367"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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.<\/jats:p>\n                <jats:p>Here, we investigated whether alterations in six previously MS-associated biomarkers are detectable and associate to underlying genetic susceptibility in two independent sample collections comprising people with MS (pwMS), healthy controls, and asymptomatic first-degree relatives of pwMS from the Genes &amp; 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).<\/jats:p>\n                <jats:p>None of the proteins demonstrated associations with MS. A composite score constructed from externally derived effect estimates was not associated with MS status in either collection or in meta-analysis. Among asymptomatic first-degree relatives, the composite score was not significantly associated with group status. In contrast, an inverse correlation between SPP1 and the MS genetic risk score among GEMS participants was found (\u03b2 = -0.246, p = 0.001).<\/jats:p>\n                <jats:p>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, and further work is needed to determine whether circulating immune signatures can capture the earliest stages of MS in at-risk individuals.<\/jats:p>","DOI":"10.64898\/2026.04.25.715317","type":"posted-content","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:08:46Z","timestamp":1777511326000},"source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of potential serum biomarkers for individuals at risk of multiple sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2775-5932","authenticated-orcid":false,"given":"Kristin","family":"Mounts","sequence":"first","affiliation":[{"name":"Center for Translational & Computational Neuroimmunology, Division of Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, 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Translational Research, Columbia University Medical Center, New York, NY, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5994-3535","authenticated-orcid":false,"given":"Nyater","family":"Ngouth","sequence":"additional","affiliation":[{"name":"Neuroimmunology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6536-4513","authenticated-orcid":false,"given":"Sonya U.","family":"Steele","sequence":"additional","affiliation":[{"name":"Neuroimmunology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, United 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National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2628-4334","authenticated-orcid":false,"given":"Daniel S.","family":"Reich","sequence":"additional","affiliation":[{"name":"Neuroimmunology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[{"name":"Center for Translational & Computational Neuroimmunology, Division of Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"Multiple Sclerosis Center, Division of Neuroimmunology, Department of Neurology, Columbia University Irving Medical 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