Melamud, E. | bioRxiv Science

bioRxiv2025

Platform-dependent effects of genetic variants on plasma APOL1 and their implications for kidney disease

Mutations in apolipoprotein L1 (APOL1) are strongly associated with protection against parasitic infections and increased risk of kidney disease in individuals of African ancestry. To better understand the mechanisms underlying APOL1-related pathologies, we examined genetic drivers of circulating APOL1 in individuals of African and European ancestry from four independent cohorts (UK Biobank, AASK, deCODE, and Health ABC) using three proteomic technologies (Olink, SomaLogic, and mass spectrometry). We found that disease-associated APOL1 G1 and G2 variants are strong cis-pQTLs for plasma APOL1 measured by Olink and SomaLogic, but not mass spectrometry. Critically, the direction of variant effects differed between proteomic platforms, being positive with Olink and negative with SomaLogic. We identified an additional APOL1 missense variant (rs2239785), common in Europeans, exhibiting the same platform-dependent directional discrepancy. Furthermore, variants in the kallikrein-kinin system (KKS), involving KLKB1, F12, and KNG1, and their genetic interactions showed strong trans-pQTL effects on APOL1 measured by Olink, but not SomaLogic. These platform-dependent discrepancies raise the possibility that both intrinsic APOL1 mutations and extrinsic KKS activity induce conformational changes in the APOL1 protein that are differentially recognized by the proteomic platforms.

genetics↗

bioRxiv2023

The Molecular Architecture of Variable Lifespan in Diversity Outbred Mice

To unravel the causes and effects of aging we can monitor the time-evolution of the aging process and learn how it is structured by genetic and environmental variation before ultimately testing theories about the causal drivers of aging. Diverse Outbred (DO) mice provide widespread, yet controlled, genetic variation generating considerable variation in mouse lifespan - here, we explore the relationship between DO mouse aging and lifespan. We profiled the plasma multiome of 110 DO mice at three ages using liquid chromatography - mass spectrometry (LC-MS)-based metabolomics and lipidomics and proteomics. Individual mice varied more than two-fold in natural lifespan. The combination of known age and resulting lifespan allows us to evaluate alternative models of how molecules were related to chronological age and lifespan. The majority of the aging multiome shifts with chronological age highlighting the accelerating chemical stress of aging. In contrast, proteomic pathways encompassing both well-appreciated aspects of aging biology, such as dysregulation of proteostasis and inflammation, as well as lesser appreciated changes such as through toll-like receptor signaling, shift primarily with fraction of life lived (the ratio of chronological age to lifespan). This measure, which approximates biological age, varies greatly across DO mice creating a global disconnect between chronological and biological age. By sampling mice near their natural death we were able to detect loss-of-homeostasis signatures involving focal dysregulation of proteolysis and the secreted phosphoproteome which may be points-of-failure in DO aging. These events are succeeded by massive changes in the multiome in mices final three weeks as widespread cell death reshapes the plasma of near-death mice.

systems biology↗