Longitudinal repeated protein measurements in a multiethnic cohort identify novel diabetes biomarkers that reveal unique disease pathways

Abstract

Circulating diabetes biomarkers have been identified with proteomics measured at a single timepoint, but what is additionally provided by longitudinal repeated measurements in the same individuals, over many years, is unknown. We studied participants in the Multi-Ethnic Study of Atherosclerosis (MESA; N=5,322, mean baseline age 61.7 years) at exams 1 (2000-2002), 5 (2010-2012), and 6 (2016-2018) profiled with Olink 3K. Associations with incident diabetes, mostly of type 2, were modeled using Cox proportional hazards with exam 1 proteins (i.e., single timepoint) and time-updating Cox with proteins from all 3 exams (i.e., longitudinal repeated) adjusted for clinical risk factors. We identified 27 novel single-timepoint associations and up to a 4-fold increase in longitudinal associations (FDR<0.05) with a proportional increase in the number consistent with causality via cis-Mendelian Randomization (~5%) and a smaller overlap in MESA longitudinal versus single associations with UK Biobank single timepoint findings (42% versus 87%, respectively). Compared to small molecule metabolism pathway enrichment among the shared proteins, proteins unique to the longitudinal analyses enriched for protein and cellular processing pathways. We conclude that longitudinal repeated measurements identify a number of distinct disease biomarkers, in part by revealing the progression of relevant biological processes within an individual closer to clinical diabetes diagnosis versus single measurements.