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Circulating microRNA Associated to Different Stages of Liver Steatosis in Prader-Willi Syndrome and Non-Syndromic Obesity.

ABSTRACT: BACKGROUND:Prader-Willi syndrome (PWS) is a rare and poorly characterized disease. Recent genomic and transcriptomic studies contributed to elucidate the molecular bases of the syndrome. In this study, we characterized the expression of circulating miRNAs in patients with PWS compared to those with non-syndromic obesity in association with liver steatosis. METHODS:MiRNAs were studied by qRT-PCR in serum samples from 30 PWS and 30 non-syndromic obese subjects. RESULTS:MiRNA expression was associated with the presence of the syndrome and to the grade of liver steatosis. MiR-122-5p, miR-151a, miR-92a-3p were up-regulated in obese (4.38-fold, p < 0.01; 2.72-fold, p < 0.05; 1.34-fold p < 0.05, respectively) and were able to differentiate obese from PWS (AUC = 0.81, sens/spec 78/71%). When stratifying groups according to the presence of steatosis, the expression of miR-151a-5p, miR-92a-3p, miR-106b-5p, and miR-93-5p were lower in PWS with steatosis grade 1. Within the group with steatosis grade 1, miR-151a-5p was significantly distinguished PWS from obese (AUC = 0.85, sens/spec 80/85%) and the combination of miR-106b-5p and miR-93-5p showed higher performances in discriminating different grades of steatosis in PWS (AUC = 0.84, sens/spec 93/74%). CONCLUSIONS:MiRNAs represent a tool to better classify and characterize PWS, providing new information about the clinical picture and the extent of steatosis.

SUBMITTER: Pratama MY

PROVIDER: S-EPMC7230920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionPrader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique physical, endocrine, and metabolic traits associated with severe obesity. Identifying liver steatosis in PWS is challenging, despite its lower prevalence compared to non-syndromic obesity. Reliable biomarkers are crucial for the early detection and management of this condition associated with the complex metabolic profile and cardiovascular risks in PWS.MethodsCirculating proteome profiling was conducted in 29 individuals with PWS (15 with steatosis, 14 without) using the Olink Target 96 metabolism and cardiometabolic panels. Correlation analysis was performed to identify the association between protein biomarkes and clinical variables, while the gene enrichment analysis was conducted to identify pathways linked to deregulated proteins. Receiver operating characteristic (ROC) curves assessed the discriminatory power of circulating protein while a logistic regression model evaluated the potential of a combination of protein biomarkers.ResultsCDH2, CTSO, QDPR, CANT1, ALDH1A1, TYMP, ADGRE, KYAT1, MCFD, SEMA3F, THOP1, TXND5, SSC4D, FBP1, and CES1 exhibited a significant differential expression in liver steatosis, with a progressive increase from grade 1 to grade 3. FBP1, CES1, and QDPR showed predominant liver expression. The logistic regression model, -34.19 + 0.85 * QDPR*QDPR + 0.75 * CANT1*TYMP - 0.46 * THOP1*ALDH1A, achieved an AUC of 0.93 (95% CI: 0.63-0.99), with a sensitivity of 93% and specificity of 80% for detecting steatosis in individuals with PWS. These biomarkers showed strong correlations among themselves and were involved in an interconnected network of 62 nodes, related to seven metabolic pathways. They were also significantly associated with cholesterol, LDL, triglycerides, transaminases, HbA1c, FLI, APRI, and HOMA, and showed a negative correlation with HDL levels.ConclusionThe biomarkers identified in this study offer the potential for improved patient stratification and personalized therapeutic protocols.

Project description:Prader-Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). The syndrome is considered the most common genetic cause of obesity, occurring in 1:10,000-1:30,000 live births. Its main characteristics include neonatal hypotonia, poor feeding, and lack of appetite in infancy, followed by weight gain, lack of satiety, and uncontrolled appetite, frequently after the age of 2-3 years. The clinical picture includes short stature, multiple endocrine abnormalities (hypogonadism, growth hormone/insulin-like growth factor-I axis dysfunction, hypothyroidism, central adrenal insufficiency), dysmorphic features, scoliosis, osteoporosis, mental retardation, and behavioral and psychiatric problems. Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake. In fact, PWS subjects die prematurely from complications conventionally related to obesity, including diabetes mellitus, metabolic syndrome, sleep apnea, respiratory insufficiency, and cardiovascular disease. The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. Consequently, dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS. In spite of all available therapeutic tools, however, successful weight loss and maintenance are hardly accomplished. In this context, clinical trials with new drugs have been initiated in order to find new possibilities of a therapy for obesity in these patients. The preliminary results of these studies seem to be encouraging. On the other hand, until well-proven medical treatments are available, bariatric surgery can be taken into consideration, especially in PWS patients with life-threatening comorbidities.

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Circulating microRNA Associated to Different Stages of Liver Steatosis in Prader-Willi Syndrome and Non-Syndromic Obesity.

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