Biology subjects

Dapas, M.

Publications and source records attributed to Dapas, M..

4 recordsLinked to original sources

bioRxiv2026

CX3CR1 And MHCII Define Distinct Synovial Macrophage Populations With Conserved Inflammatory Response Across Mouse Models Of Rheumatoid Arthritis.

Macrophages in the synovial lining are critical for the maintenance of healthy tissue while also contributing to the pathogenesis of rheumatoid arthritis (RA). However, the field currently lacks a unifying characterization of synovial macrophage heterogeneity across steady-state and inflammation. Here, we defined 4 transcriptionally distinct populations of synovial macrophages CX3CR1+MHCII- (lining); CX3CR1-MHCII- (interstitial/sublining); CX3CR1-MHCII+ (monocyte-derived); and CX3CR1+MHCII+ (infiltrating). The MHCII-populations are long-lived and derived from embryonic precursors regardless of localization while the MHCII+ populations differentiate from bone marrow (BM) progenitors dependent on CCR2. We identified conserved activation pathways between acute and chronic mouse models of inflammatory arthritis as well as novel arthritis-associated subpopulations. During peak inflammation, the influx of BM-derived cells was associated with upregulation of monocyte-related genes with concurrent down-regulation of tissue-resident genes. Our results provide a unifying schema for describing synovial macrophages across conditions and pave the way for future studies in modulating transcriptional activity in rheumatoid arthritis.

immunology↗

bioRxiv2026

Circulating Immune Cells are Associated with Non-Inflammatory Pain in Rheumatoid Arthritis

Over half of patients with rheumatoid arthritis (RA) report clinically meaningful pain, despite treatment with disease-modifying antirheumatic drugs (DMARDs). While joint inflammation is a known cause of pain in patients with rheumatic diseases, emerging data indicate that many patients also suffer from centralized or nociplastic pain. There is a critical unmet need to characterize the altered cellular state that distinguishes patients with centralized pain. In the IMPACT study, 39 RA patients with minimal joint inflammation but varying levels of pain underwent quantitative sensory testing (QST) to assess nociplastic pain, completed patient-reported outcome (PRO) surveys, and provided blood samples for immune profiling. Supervised and unsupervised analysis of the multi-parameter spectral flow cytometry data identified immune cell populations correlated with nociplastic pain and patient-reported pain intensity. Moreover, analyses of single-cell RNA-seq from a subset of 22 patients revealed differences in cell type proportions and differential expression between the high and low pain groups. These studies provide novel insights into the role of circulating immune cells in altered central nervous system (CNS) pain regulation in adults with RA.

immunology↗

bioRxiv2019

Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

BackgroundPolycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS.\n\nMethods and FindingsUnsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped discovery cohort of 893 PCOS cases and an ungenotyped validation cohort of 263 PCOS cases. We identified two PCOS subtypes: a \"reproductive\" group (21-23%) characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low body mass index (BMI) and insulin levels; and a \"metabolic\" group (37-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in four novel loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN1, P=2.2x10-10; IQCA1, P=2.8x10-9; BMPR1B/UNC5C, P=9.7x10-9; CDH10, P=1.2x10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P=1.0x10-8). We have previously reported that rare variants in DENND1A, a gene regulating androgen biosynthesis, were associated with PCOS quantitative traits in a family-based whole genome sequencing analysis. We classified the reproductive and metabolic subtypes in this family-based PCOS cohort and found that the subtypes tended to cluster in families and that carriers of rare DENND1A variants were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.\n\nConclusionsIn conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, these subtypes were associated with novel susceptibility loci. Our results suggest that these subtypes are biologically relevant since they have distinct genetic architectures. This study demonstrates how precise phenotypic delineation can be more powerful than increases in sample size for genetic association studies.

genomics↗

bioRxiv2018

Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in pathogenesis of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is a leading risk factor for type 2 diabetes in young women. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. To test the hypothesis that rare genetic variants contribute to PCOS pathogenesis, we performed whole-genome sequencing on DNA from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31x10-5, Padj=0.019) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

genomics↗