Biology subjects

Rajeevan, N.

Publications and source records attributed to Rajeevan, N..

4 recordsLinked to original sources

bioRxiv2026

Blood-to-tissue translation in autoimmune disease: paired single-cell evidence from systemic sclerosis

AO_SCPLOWBSTRACTC_SCPLOWThe biology that governs progression and therapeutic response in autoimmune disease is organized in affected tissue, but direct molecular readout of that biology requires invasive biopsy and is rarely repeated during clinical trials or routine care. Using paired blood-skin single-cell RNA-sequencing from a systemic sclerosis (SSc) cohort of 74 individuals (57 patients and 17 matched controls, 192,809 cells across 53 annotated cell states), we show that peripheral blood carries a recoverable projection of tissue-resident molecular state. Across 63 pathways scored in both compartments, 43 same-pathway blood-skin associations reach FDR < 0.05; at cell-type resolution, 212 cross-compartment associations survive residualization for disease status and sex. Per-patient classifiers recover tissue-defined molecular states out of fold with AUCs between 0.62 and 0.79, with the strongest recoveries on fibroblast subtype programs that have no direct circulating analog: fibroblast COMP at 0.79, COCH at 0.75, MYOC2 at 0.74, POSTN at 0.74. Tissue programs route through different blood compartments at different representational levels: fibroblast programs resolve through T-cell, Treg, monocyte and B-cell axes at compositional and distributional levels, while interferon resolves through expression state across multiple cell types. Within SSc alone, a cross-validated partial least squares model learns a shared blood-skin latent axis at r = 0.486 (permutation p = 0.006); the induced patient ranking recovers tissue-interferon-high patients at 86% precision at the top-20% screening threshold against a 50% base rate. A paired multiview autoencoder, trained on module-level dependency structure under contrastive alignment, paired reconstruction, neighborhood preservation and tissue-target supervision, learns a shared latent geometry in which blood-only projections land in the same tissue-state region as their matched tissue samples and supports recovery of held-out tissue targets above simpler baselines and above two permutation null families. These results map the empirical geometry of cross-compartment inference in autoimmune disease and position peripheral blood as a substrate for tissue-state inference at trial and clinical scale.

immunology↗

bioRxiv2025

Exploratory Multi-Omics Profiling of Rheumatoid Arthritis Heterogeneity

Rheumatoid arthritis (RA) is a clinically heterogeneous disease with highly variable treatment responses despite widespread use of conventional and biologic disease-modifying therapies. Existing clinical and serological markers only partially explain this variability and are not routinely used to personalise drug choice. We hypothesised that integrated plasma proteomic- metabolomic profiling could capture dimensions of RA molecular heterogeneity that are invisible to standard phenotyping and highlight characteristic patterns of metabolic dysregulation. We profiled 384 proteins and 1,063 metabolites in 80 RA patients and 40 healthy controls. Unsupervised consensus clustering of the integrated omics matrix identified two stable molecular subtypes within the RA cohort. Anti-citrullinated protein antibody (ACPA) status, which in this cohort was evenly split overall (40 ACPA-positive, 40 ACPA-negative), was similarly distributed across the two subtypes, suggesting that the molecular groupings reflect heterogeneity orthogonal to conventional serology. Protein-metabolite association network analysis revealed a substantial reduction in association edges in RA versus controls, with pathway-specific effects: pronounced connectivity loss in amino-acid metabolism but paradoxical gains in inflammatory mediators including glutamate and sphingolipids. Preserved correlation strength among surviving edges is consistent with selective pathway disconnection rather than uniformly weakened coordination. These hypothesis-generating findings, limited by cross-sectional design, medication heterogeneity, and single-centre recruitment, suggest that RA comprises molecularly distinct subtypes not captured by standard serological categories and is associated with extensive metabolic network reorganisation. This multi-omics framework illustrates how network-level signatures could support future precision stratification efforts and motivates further investigation of metabolic network restoration as a potential therapeutic avenue.

immunology↗

bioRxiv2024

Shroom3-Rock interaction and profibrotic function: Resolving mechanism of an intronic CKD risk allele.

Common intronic enhancer SNPs in Shroom3 associate with CKD in GWAS, although there is paucity of detailed mechanism. Previously, we reported a role for Shroom3 in mediating crosstalk between TGF{beta}1- & Wnt/Ctnnb1 pathways promoting renal fibrosis (TIF). However, beneficial roles for Shroom3 in proteinuria have also been reported suggesting pleiotropic effects. Here we focused on identifying the specific profibrotic Shroom3 motif. Given known therapeutic roles for Rho-kinase inhibitors in experimental CKD, and the established interaction between Shroom3 and Rock via its ASD2 domain, we hypothesized that Shroom3-mediated ROCK activation played a crucial role in its profibrotic function in high expressors. To test this hypothesis, we developed transgenic mice and cell lines that inducibly overexpressed wild-type- (WT-Sh3) or ASD2-domain deletion- Shroom3 (ASD2{Delta}-Sh3). Prior scRNAseq data showed that during TIF, Shroom3 and Rock co-expression occurred in injured tubular cells and fibroblasts, highlighting cell-types where this mechanism could be involved. Using HEK293T cells, we first confirmed absent ROCK binding and inhibited TGF{beta}1-signaling with ASD2{Delta}-Sh3-overexpression vs WT-Sh3. In mIMCD cells, ASD2{Delta}-Sh3 overexpression, reduced Rock activation (phospho-MYPT1), pro-fibrotic and pro-inflammatory transcripts vs WT-Sh3. Fibroblast proliferation (3T3) was also reduced with ASD2{Delta}-Sh3. In vivo, we studied ureteric obstruction (UUO) and Aristolochic nephropathy (AAN) as TIF models. In AAN, inducible global-, or Pan-tubular specific-, WTSh3-overexpression showed increased azotemia, and TIF vs ASD2{Delta}-Sh3 mice. WT-Sh3 mice consistently showed significant enrichment of Rho-GTPase, TGF{beta}1- and Wnt/CtnnB1- signaling in kidney transcriptome, paralleling Shroom3-coexpressed genes in tubulo-interstitial transcriptomes from human CKD. In UUO, again WT-Sh3 mice recapitulated increased fibrosis vs ASD2{Delta}-Sh3. Importantly, ASD2{Delta}-Sh3 did not develop albuminuria vs WT-Sh3, while mutating a disparate Fyn-binding Shroom3 motif induced albuminuria in mice, suggesting motif-specific roles for Shroom3 in the kidney. Hence, our data show a critical role for the Rock-binding, ASD2-domain in mediating TIF in milieu of Shroom3 excess, with relevance to human CKD.

systems biology↗

bioRxiv2022

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program

The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic change over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). The MVP was divided into five birth cohorts (N-range=123,888 [born from 1943-1947] to 136,699 [born from 1948-1953]). Groups of participants were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP+HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010<Cohens d<0.259, p<7.80x10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept=1.08{+/-}0.042). The 1kGP+HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction=0.045{+/-}0.007, p<0.05) confounding in the GWAS statistics. This study provides a comprehensive characterization of ancestry diversity of the MVP cohort over time and highlights that more refined modeling of genetic diversity (e.g., the 1kGP+HGDP-based ancestry assignment) can more accurately capture the polygenic architecture of traits and diseases that could be affected by population stratification.

genomics↗