👤 Vinicius Lima Vazquez

Effective solutions to obesity remain elusive, partly owing to its root in a positive energy balance (EB), which stems from the interplay of numerous traits spanning body size and composition, diet, physical activity, and metabolic profile. Nevertheless, EB-contributing traits are typically studied in isolation. We integrate numerous EB-related traits measured in the UK Biobank to uncover the underlying patterns of EB and associated genes in study participants. We used sparse factor analysis to integrate traits and performed genome-wide association analyses on the integrated phenotypes to elucidate EB-related genes and metabolic pathways. We performed pleiotropy analyses on candidate single-nucleotide polymorphisms to uncover the genetic basis of EB. We identified multiple genes and genomic regions associated with EB, including many that have previously not been directly associated with obesity measures (e.g., MIR5591, FNDC3B, ANAPC10, SULT1A1, AXIN1, SKIDA1, ERLIN1, DOCK7), which we validated using an independent subset of the UK Biobank dataset along with data from the Atherosclerosis Risk in Communities cohort. We found that the covariances in EB traits are primarily driven by genome-wide pleiotropic associations. We offer new insight into EB patterns and the genetic basis of EB. Show less

Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals. Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays. The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function. In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers. Show less

Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&C region. Show less

Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer. Show less

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features. Show less

Progressive vision loss in adults has become increasingly prevalent worldwide due to retinopathies associated with aging, genetics, and epigenetic factors that damage the retinal microvasculature. Insufficient supply of oxygen and/or nutrients upregulates factors such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), which can induce abnormal angiogenesis and damage the structural arrangement of the retinal blood barrier (BRB). Müller glia (MG) regulate the diffusion of essential compounds across the BRB and respond to retinal insults via reactive gliosis, which includes cell hypertrophy, migration, and/or proliferation near areas of elevated VEGF concentration. Increasing concentrations of exogenous VEGF, upregulated by retinal pigmented epithelium cells, and endogenous epidermal growth factor receptor (EGF-R) stimulation in MG, implicated in MG proliferative and migratory behavior, often lead to progressive and permanent vision loss. Our project examined the chemotactic responses of the rMC-1 cell line, a mammalian MG model, toward VEGF and EGF signaling fields in transwell assays, and within respective concentration gradient fields produced in the glia line (gLL) microfluidic system previously described by our group. rMC-1 receptor expression in defined ligand fields was also evaluated using quantitative polymerase chain reaction (qPCR) and immunocytochemical staining. Results illustrate dramatic increases in rMC-1 chemotactic responses towards EGF gradient fields after pre-treatment with VEGF. In addition, qPCR illustrated significant upregulation of EGF-R upon VEGF pre-treatment, which was higher than that induced by its cognate ligand, EGF. These results suggest interplay of molecular pathways between VEGF and EGF-R that have remained understudied in MG but are significant to the development of effective anti-VEGF treatments needed for a variety of retinopathies. Show less

Emerging therapies have begun to evaluate the abilities of Müller glial cells (MGCs) to protect and/or regenerate neurons following retina injury. The migration of donor cells is central to many reparative strategies, where cells must achieve appropriate positioning to facilitate localized repair. Although chemical cues have been implicated in the MGC migratory responses of numerous retinopathies, MGC-based therapies have yet to explore the extent to which external biochemical stimuli can direct MGC behavior. The current study uses a microfluidics-based assay to evaluate the migration of cultured rMC-1 cells (as model MGC) in response to quantitatively-controlled microenvironments of signaling factors implicated in retinal regeneration: basic Fibroblast Growth factor (bFGF or FGF2); Fibroblast Growth factor 8 (FGF8); Vascular Endothelial Growth Factor (VEGF); and Epidermal Growth Factor (EGF). Findings indicate that rMC-1 cells exhibited minimal motility in response to FGF2, FGF8 and VEGF, but highly-directional migration in response to EGF. Further, the responses were blocked by inhibitors of EGF-R and of the MAPK signaling pathway. Significantly, microfluidics data demonstrate that changes in the EGF gradient (i.e. change in EGF concentration over distance) resulted in the directional chemotactic migration of the cells. By contrast, small increases in EGF concentration, alone, resulted in non-directional cell motility, or chemokinesis. This microfluidics-enhanced approach, incorporating the ability both to modulate and asses the responses of motile donor cells to a range of potential chemotactic stimuli, can be applied to potential donor cell populations obtained directly from human specimens, and readily expanded to incorporate drug-eluting biomaterials and combinations of desired ligands. Show less