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Identification of Genetic Variants in 65 Obesity Related Genes in a Cohort of Portuguese Obese Individuals.

ABSTRACT: Obesity is a major public health problem, which has a strong genetic component that interplays with environmental factors. Several genes are known to be implicated in the regulation of body weight. The identification of alleles that can be associated with obesity is a key element to control this pandemic. On the basis of a Portuguese population, 65 obesity-related genes are sequenced using Next-Generation Sequencing (NGS) in 72 individuals with obesity, in order to identify variants associated with monogenic obesity and potential risk factors. A total of 429 variants are identified, 129 of which had already been associated with the phenotype. Comparing our results with the European and Global frequencies, from 1000 Genomes project, 23 potential risk variants are identified. Six new variants are discovered in heterozygous carriers: four missense (genes ALMS1-NM_015120.4:c.5552C>T; SORCS1-NM_001013031.2:c.1072A>G and NM_001013031.2: c.2491A>C; TMEM67-NM_153704.5:c.158A>G) and two synonymous (genes BBS1-NM_024649.4:c.1437C>T; TMEM67-NM_153704.5:c.2583T>C). Functional studies should be performed to validate these new findings and evaluate their penetrance and pathogenicity. Regardless of no cases of monogenic obesity being identified, this kind of investigational study is important when we are still trying to understand the aetiology and pathophysiology of obesity. This will allow the identification of rare variants associated with obesity and the study of their prevalence in specific populational groups.

SUBMITTER: Ginete C

PROVIDER: S-EPMC8073382 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOvine footrot caused by Dichelobacter nodosus (D. nodosus) is a contagious disease with serious economic and welfare impacts in sheep production systems worldwide. A better understanding of the host genetic architecture regarding footrot resistance/susceptibility is crucial to develop disease control strategies that efficiently reduce infection and its severity. A genome-wide association study was performed using a customized SNP array (47,779 SNPs in total) to identify genetic variants associated to footrot resistance/susceptibility in two Portuguese native breeds, i.e. Merino Branco and Merino Preto, and a population of crossbred animals. A cohort of 1375 sheep sampled across 17 flocks, located in the Alentejo region (southern Portugal), was included in the analyses.ResultsPhenotypes were scored from 0 (healthy) to 5 (severe footrot) based on visual inspection of feet lesions, following the Modified Egerton System. Using a linear mixed model approach, three SNPs located on chromosome 24 reached genome-wide significance after a Bonferroni correction (p < 0.05). Additionally, six genome-wide suggestive SNPs were identified each on chromosomes 2, 4, 7, 8, 9 and 15. The annotation and KEGG pathway analyses showed that these SNPs are located within regions of candidate genes such as the nonsense mediated mRNA decay associated PI3K related kinase (SMG1) (chromosome 24) and the RALY RNA binding protein like (RALYL) (chromosome 9), both involved in immunity, and the heparan sulfate proteoglycan 2 (HSPG2) (chromosome 2) and the Thrombospodin 1 (THBS1) (chromosome 7) implicated in tissue repair and wound healing processes.ConclusionThis is the first attempt to identify molecular markers associated with footrot in Portuguese Merino sheep. These findings provide relevant information on a likely genetic association underlying footrot resistance/susceptibility and the potential candidate genes affecting this trait. Genetic selection strategies assisted on the information obtained from this study could enhance Merino sheep-breeding programs, in combination with farm management strategies, for a more effective and sustainable long-term solution for footrot control.

Project description:Although lifestyle and physiology in obese individuals are accepted to lead to changes in the intestinal microbiota, uncertainty remains about microbiota dysbiosis, and xenobiotics intake, as a source of selective pressure, independent of antimicrobial chemotherapy. The aim of this study was to compare the occurrence of antimicrobial resistance genetic markers (ARG) in faecal specimens of eutrophic, overweight and obese individuals, and their correlation with xenobiotic intake and gut bacteria density. Methods: This was a cross-sectional case-controlled study including 72 adult participants with no record of intestinal or systemic diseases, or recent use of antimicrobials, grouped as eutrophic, overweight, or obese. Anthropometric profile, eating habits and oral xenobiotics intake were recorded. Faecal metagenomic DNA was used to screen for ARG by PCR, and to measure bacterial groups by fluorescence in situ hybridization (FISH). Student's t and Wilcoxon tests were used to compare means and differences in ARG detection (95% confidence intervals). Correlation analyses (odds ratio) and relationships between bacteria density and ARG were determined. Results: Increase in abdominal circumference, waist circumference, hip, waist-hip ratio, BMI, carbohydrate, fibres, and total calorie intakes were different from eutrophic to obese participants. Habitual use of antihypertensive and anti-inflammatory drugs, antacids, and artificial sweeteners were associated mainly with obesity and overweight. Nutritional supplements were associated to the eutrophic group. ARG screening showed differences being more frequent among obese, and positive for 27 genetic markers related to β-lactams, tetracyclines, the macrolide lincosamide and streptogramin group, quinolones, sulfonamides, aminoglycosides, and efflux pump. Positive correlation between ARG and BMI, caloric intake, and intake of xenobiotics, was observed for obese individuals. Relationships among ARG detection and bacteria densities were also different. Conclusions: This study reinforces the hypothesis that obese individuals may harbour an altered gut microbiota, if compared to eutrophic. The overweight individuals display a transitional gut microbiota which seems to be between eutrophic and obese. Furthermore, the increased xenobiotic intake associated to obesity may play an important role in the antimicrobial resistance phenomenon.

Project description:As a serious public health problem nowadays, obesity and its complications are receiving gradually more attention, especially on how food-induced obesity causes the expansion of adipose tissue and leads to the occurrence of metabolic inflammation and infiltration of immune cells. It's still worth mentioning that numerous genes in adipose tissue which differ between obese and normal individuals in food-induced obesity were not insufficiently studied. Applying machine learning methods and natural language processing methods on transcriptome datasets and PubMed abstracts, we investigated 8 genes with differential expression and high association with macrophages in the visceral and subcutaneous adipose tissue between obese and normal individuals, and meanwhile low correlation with leptin. Compared with normal group, Quantitative Real-time Polymerase Chain Reaction, Western Blot, immunohistochemistry, immunofluorescence and other subsequent animal experiments on the 8 filtered genes were applied in the adipose tissue of C57BL/6J and OB/OB mice, we found that the expression of glycoprotein IX (GP9), MHC class I polypeptide related sequence B (MICB), CDGSH iron sulfur domain 1 (CISD1) and Pre-mRNA-processing factor 19 (PRPF19) in protein level were down-regulated in visceral fat of obese mice induced by high-fat diet. And these obese mice showed decreased levels of mannosidase alpha class 2B member 1 (MAN2B1) and TYRO protein tyrosine kinase binding protein (TYROBP) in their subcutaneous adipose tissue, while phosphate and tension homology deleted on chromosome pten (PTEN) and eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) had been sufficiently studied. The pattern in OB/OB mouse was dramatically different with these patterns. Through double immunofluorescence staining, it was found that all genes were co-localized with CD206, which was the marker of M1 and M2 macrophage in adipose tissue. Further interacting drugs for the genes were calculated and subsequently circumin and beta-catonin were proved to be interacting with these genes and functioned in inhibiting food-induced obesity. Further knowledge gragh was constructed to illustrate the relationship between obesity, filtered genes, drugs and related concepts. To summarize our findings, we discovered some new differential genes in adipose tissue which could potentially establish a new connection between adipose tissue macrophages and food-induced obesity. Furthermore, they offered unique insights into exploring the mechanism of adipose tissue genes related to food-induced obesity and related diseases.

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Identification of Genetic Variants in 65 Obesity Related Genes in a Cohort of Portuguese Obese Individuals.

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