Biology subjects

Kavousi, M.

Publications and source records attributed to Kavousi, M..

5 recordsLinked to original sources

bioRxiv2025

A Novel FNDC1-NAMPT-NAD axis is Implicated in Small and Large-vessel Arterial Disease and Drives Vascular Calcification

Vascular calcification represents a convergent pathological feature of diverse cardiovascular diseases, yet the upstream molecular programs orchestrating this process remain poorly defined. Here, we uncover fibronectin type III domain-containing 1 (FNDC1) as a previously unrecognized regulator of vascular calcification across both microvascular and macrovascular beds. Integrative transcriptomic profiling of human calciphylaxis lesions and atherosclerotic coronaries identified FNDC1 as one of the most significantly upregulated genes. In primary human vascular smooth muscle cells, FNDC1 drove osteogenic phenotype switch and vascular calcification through activation of PI3K/AKT signaling and metabolic reprogramming. Mechanistically, FNDC1 directly binds to nicotinamide phosphoribosyltransferase (NAMPT) resulting in elevated intracellular NAD levels, thus coupling vascular signaling to control of NAD biosynthesis. In murine models, genetic deletion of Fndc1 or pharmacologic inhibition of NAMPT suppressed arterial calcification and prolonged survival. Clinically, circulating FNDC1 levels were elevated in patients with both calciphylaxis and coronary artery disease and independently predicted cardiovascular risk in 42,687 UK Biobank participants. Together, these findings establish FNDC1 as a central mediator of vascular pathology and highlight the FNDC1- NAMPT-NAD+ axis as a promising target for therapeutic intervention.

cell biology↗

bioRxiv2022

Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

Coronary artery disease (CAD) and atherosclerosis are characterized by plaque formation in the arteries wall. CAD progression involves complex interactions and phenotypic plasticity within and between distinct vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but the reported cell phenotypes in humans remain controversial. Here, we meta-analyzed four scRNA-seq datasets, creating the first map of human cell diversity in atherosclerosis. We generated an atlas of 118,578 high-quality cells, characterized cell-type diversity and provided insights into smooth muscle cell (SMC) phenotypic modulation, transcription factor activity and cell-cell communication. We integrated genome-wide association study (GWAS) data and uncovered a critical role for modulated SMC phenotypes in CAD and coronary calcification. Finally, we identified candidate markers of fibromyocyte and fibrochondrogenic human SMCs (LTBP1 and CRTAC1) that may serve as proxies of atherosclerosis progression. Altogether, we created a unified cellular map of atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.

genomics↗

bioRxiv2022

FHL5 controls vascular disease-associated gene programs in smooth muscle cells

BackgroundGenome-wide association studies (GWAS) have identified hundreds of loci associated with common vascular diseases such as coronary artery disease (CAD), myocardial infarction (MI), and hypertension. However, the lack of mechanistic insights for a majority of these loci limits translation of these findings into the clinic. Among these loci with unknown functions is UFL1-FHL5 (chr6q16.1), a locus that reached genome-wide significance in a recent CAD/MI GWAS meta-analysis. In addition to CAD/MI, UFL1-FHL5 is also implicated to coronary calcium, intracranial aneurysm, and migraine risk, consistent with the widespread pleiotropy observed among other GWAS loci. MethodsWe apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and imaging of human coronary artery tissues to implicate Four-and-a-half LIM domain 5 (FHL5) as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments. ResultsWe prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through eQTL colocalization methods. FHL5 gene expression was enriched in the SMC and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating SMC contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream CAD/MI loci, such as FOXL1 and FN1 that have roles in vascular remodeling. ConclusionTaken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling loci. These trans-acting mechanisms may account for a portion of the heritable risk for complex vascular diseases.

genomics↗

bioRxiv2021

Long-term association of pregnancy and maternal brain structure: the Rotterdam Study

The peripartum period is the highest risk interval for the onset or exacerbation of psychiatric illness in womens lives. Notably, pregnancy and childbirth have been associated with short-term structural and functional changes in the maternal human brain. Yet the long-term effects of parity on maternal brain structure remain unknown. Therefore, we utilized a large population-based cohort to examine the association between parity and brain structure. In total, 2,835 women (mean age 65.2 years; all free from dementia, stroke, and cortical brain infarcts) from the Rotterdam Study underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Associations of parity with global and lobar brain tissue volumes, white matter microstructure, and markers of vascular brain disease were examined using regression models. We found that parity was associated with a larger global gray matter volume ({beta}= 0.14, 95% CI = 0.09-0.19), a finding that persisted following adjustment for sociodemographic factors. A non-significant dose-dependent relationship was observed between a higher number of childbirths and larger gray matter volume. The gray matter volume association with parity was globally proportional across lobes. No associations were found regarding white matter volume or integrity, nor with markers of cerebral small vessel disease. The current findings indicate that pregnancy and childbirth are associated with robust long-term changes in brain structure involving larger global gray matter volume that persists for decades. Taken together, these data provide novel insight into the impact of motherhood on the human brain.

neuroscience↗

bioRxiv2019

KCND3 is a novel susceptibility locus for early repolarization

The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.\n\nIn this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

genetics↗