Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map these signals, eQTLBMA to discover GLOM- or TI-specific eQTLs, and single-cell RNA-seq data of control kidney tissue to identify the cell type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IgAN) GWAS to perform a transcriptome-wide association study (TWAS). We discovered 894 GLOM eQTLs and 1,767 TI eQTLs at FDR < 0.05. 14% and 19% of GLOM and TI eQTLs, respectively, had >1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM specific and TI specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IgAN TWAS identified significant GLOM and TI genes, primarily at the HLA region. In this study, we discovered GLOM and TI eQTLs, identified those that were tissue specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are available for browsing and download via our eQTL browser, "nephQTL."

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Background Health outcomes in rheumatoid arthritis (RA) have improved significantly over the past two decades. However, research suggests that disparities exist by race/ethnicity and socioeconomic status, with certain vulnerable populations remaining understudied. Our objective was to assess disparities in disease activity and function by race/ethnicity and explore the impact of language and immigrant status at clinics serving diverse populations. Methods A cross-sectional study of 498 adults with confirmed RA at two rheumatology clinics, a university hospital clinic and a public county hospital clinic. Outcomes included the Disease Activity Score 28 (DAS-28), its components, and a measure of function, the Health Assessment Questionnaire (HAQ). We estimated multivariable linear regression models including interaction terms for race/ethnicity and clinic site. Results After adjusting for age, gender, education, disease duration, rheumatoid factor and medication use, clinically meaningful and statistically significant differences in DAS-28 and HAQ were seen by race/ethnicity, language, and immigrant status. Lower disease activity and better function was observed among Whites compared to non-Whites at the university hospital. This same pattern was observed for disease activity by language (English compared to non-English) and immigrant status (U.S.-born compared to immigrant) at the university clinic. No significant differences in outcomes were found at the county clinic. Conclusion The relationship between social determinants and RA disease activity varied significantly across clinic setting with pronounced variation at the university, but not at the county clinic. These disparities may be a result of events that preceded access to subspecialty care, poor adherence, or healthcare delivery system differences.

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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC–ERK–SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases.