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Childhood obesity is a serious public health problem associated with the development of several chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. The elevated prevalence of obesity is mostly due to inadequate diet and lifestyle, but it is also influenced by genetic factors. To review recent advances in the field of the genetics of obesity. We summarize the list of genes associated with the rare non-syndromic forms of obesity, and explain their function. Furthermore, we discuss the technologies that are available for the genetic diagnosis of obesity. Several studies reported that single gene variants cause Mendelian forms of obesity, determined by mutations of major effect in single genes. Rare, non-syndromic forms of obesity are a result of loss-of-function mutations in genes that act on the development and function of the hypothalamus or the leptin-melanocortin pathway. These variants disrupt enzymes and receptors that play a role in energy homeostasis, resulting in severe early-onset obesity and endocrine dysfunctions. Different approaches and technologies have been used to understand the genetic background of obesity. Currently, whole genome and whole exome sequencing are important diagnostic tools to identify new genes and variants associated with severe obesity, but other approaches are also useful at individual or population levels, such as linkage analysis, candidate gene sequencing, chromosomal microarray analysis, and genome-wide association studies. The understanding of the genetic causes of obesity and the usefulness and limitations of the genetic diagnostic approaches can contribute to the development of new personalized therapeutic targets against obesity. •Most non-syndromic forms of obesity are a result of mutations in genes that act on the leptin-melanocortin pathway.•These mutations can be dominant (BDNF, NTRK2, SIM1, MC4R, SH2B1, MRAP2, LRP2) or recessive (LEP, LEPR, POMC, MCR4, PCSK1, TUB).•The genetic diagnosis of obesity can be obtained through approaches conducted at individual, familial or populational levels.•Next generation sequencing can contribute to the development of new therapeutic targets for Mendelian obesity.

•The prevalence of vitamin D deficiency was substantial in children and adolescents with type 1 diabetes mellitus.•Children and adolescents with type 1 diabetes mellitus should be encouraged to adopt healthier eating practices and routine physical exercise.•Glycemic control, physical activity, and excess weight represent risk factors for vitamin D deficiency. The therapeutic potential of vitamin D has been studied regarding adjuvant interventions. Some studies have evaluated the factors associated with vitamin D deficiency (VDD) in healthy populations, but they are scarce in children and adolescents with type 1 diabetes mellitus (T1DM). The objective of this study was to describe the prevalence of and factors associated with VDD in children and adolescents with T1DM. This was a cross-sectional analysis of the baseline data from a controlled clinical trial. Participants were between 7 and 16 y old, diagnosed with T1DM for at least 1 y, and classified as having VDD when 25-hydroxyvitamin D (25[OH]D) was less than 30 ng/mL. The following data were collected: sociodemographic, clinical, laboratory, lifestyle, anthropometric, and Fok-I polymorphism (rs2228570). A multivariable logistic regression model was developed to adjust the effect of potential confounders. The odds ratio (OR) with 95% confidence interval (CI) was used. The significance level used was 5%. A total of 143 children and adolescents were enrolled; 51% were female and the mean age was 11.5 ± 2.2 y old. The prevalence of VDD was 79% and the mean 25(OH)D of participants with VDD was 19.2 ± 6.1 ng/mL. The factors associated with VDD were low level of physical activity (OR, 2.9, 95% CI, 1.1–7.6, P = 0.031), poor glycemic control (OR, 5.0, 95% CI, 1.9–13.2, P = 0.001), and excess weight (OR, 3.6, 95% CI, 1.1–11.1, P = 0.029). A high prevalence of VDD was observed as well as some associated lifestyle and clinical variables. Recommendations for children and adolescents with T1DM include monitoring their 25(OH)D and encouraging healthy eating practices and routine physical exercise.

The COVID-19 pandemic has highlighted the crucial role of vaccines in preventing infection and reducing disease severity. However, emerging SARS-CoV-2 variants have posed challenges to vaccine-induced immunity. To evaluate the immunological response and clinical characteristics of individuals with complete and incomplete COVID-19 vaccination schedules, with a focus on neutralizing antibody levels against SARS-CoV-2 variants. A total of 245 participants were analyzed and stratified by complete and incomplete vaccination status. The complete vaccination was defined by 3 doses for <40 years or 4 doses for >40 years. Clinical data, serological responses, and neutralization levels against the Wuhan strain and the Delta and Omicron (BA.1, BA.2, BA.5) variants were evaluated. Among the participants, 71 (29%) had an incomplete vaccination schedule, and 174 (71%) had completed the recommended doses. Despite only 118 (48.2%) of participants reporting a prior positive COVID-19 test, 210 (85.7%) tested positive for anti-nucleocapsid antibodies, underscoring a high rate of undiagnosed or asymptomatic infections. Neutralization levels were reduced in incompletely vaccinated individuals, especially against the Omicron BA.2 variant (89%). A moderate-to-strong correlation was found between declining immunity and increasing time since last vaccination or infection. Older participants demonstrated lower neutralization rates against the Wuhan and Delta strains, and cross-reactivity was observed between Wuhan and Delta (r ≈ 0.7), as well as between Omicron BA.1 and BA.2. Finally, a strong negative association was observed between time since the last known SARS-CoV-2 infection and neutralization against Omicron BA.2, as well as moderate-to-strong negative correlations with Omicron BA.5 and BA.1. COVID-19 vaccination is effective in eliciting protective immunity, although immune evasion by recent Omicron subvariants and waning immunity over time remain challenges. These findings support the need for updated booster strategies and continued public health efforts to ensure full vaccine coverage and long-term protection.

Background: Regular physical activity has an important role in energy expenditure and combats the development of obesity. During exercise, PPARGC1A is overexpressed, stimulating an increase of the expression of FNDC5. This protein is cleaved to release the hormone irisin, which activates a browning process in white adipose tissue through an increase in UCP1 expression. As a result, irisin leads to mitochondrial heat production and energy expenditure. Objectives:The aim of this study was to investigate whether genetic variants in genes related to browning are associated with severe obesity and obesity-related features. This case-control study comprised 210 individuals with severe obesity (median body mass index [BMI] 45.6 [range 40.5–52.2]) and 191 normal-weight subjects (BMI 22.8 [21.1–23.9]). Methods: Genomic DNA was extracted from peripheral blood and the genotypes of the PPARGC1A(rs8192678, rs3736265, rs2970847, and rs3755863) and UCP1 (rs6536991 and rs12502572) genes were obtained using Taqman® assay. For the FNDC5 gene, screening of exons 3–5 as well as their intron-exon boundaries was performed using automatic sequencing. Results: Our results demonstrated that PPARGC1Ars2970847 and UCP1rs12502572 are associated with severe obesity. Furthermore, these polymorphisms influence anthropometric traits, such as BMI, body weight, and body adiposity index. Our findings also showed a dose-effect relationship between PPARGC1A rs8192678 and fasting plasma glucose. Finally, 5 rare mutations were identified in FNDC5, and 1 of these is a novel missense mutation. Conclusion: This study shows that genetic variants in the activation of brown-like adipocyte pathway play an important role in the susceptibility to severe obesity.

Excessive gestational weight gain (GWG) is associated with increased risk of maternal and neonatal complications. We investigated obesity-related polymorphisms in the FTO gene (rs9939609, rs17817449) and ADRB2 (rs1042713, rs1042714) as candidate risk factors concerning excessive GWG in pregnant women with pregestational diabetes. This nutrigenetic trial, conducted in Brazil, randomly assigned 70 pregnant women to one of the groups: traditional diet (n = 41) or DASH diet (n = 29). Excessive GWG was the total weight gain above the upper limit of the recommendation, according to the Institute of Medicine guidelines. Genotyping was performed using real-time PCR. Time-to-event analysis was performed to investigate risk factors for progression to excessive GWG. Regardless the type of diet, AT carriers of rs9939609 (FTO) and AA carriers of rs1042713 (ADRB2) had higher risk of earlier exceeding GWG compared to TT (aHR 2.44; CI 95% 1.03–5.78; p = 0.04) and GG (aHR 3.91; CI 95% 1.12–13.70; p = 0.03) genotypes, respectively, as the AG carriers for FTO haplotype rs9939609:rs17817449 compared to TT carriers (aHR 1.79; CI 95% 1.04–3.06; p = 0.02).

Purpose Monogenic forms of obesity are caused by single-gene variants which affect the energy homeostasis by increasing food intake and decreasing energy expenditure. Most of these variants result from disruption of the leptin–melanocortin signaling, which can cause severe early-onset obesity and hyperphagia. These mutation have been identified in genes encoding essential proteins to this pathway, including leptin ( LEP ), melanocortin 2 receptor accessory proteins 2 ( MRAP2 ) and proopiomelanocortin ( POMC ). We aimed to investigate the prevalence of LEP , MRAP2 and POMC rare variants in severely obese adults, who developed obesity during childhood. To the best of our knowledge, this is the first study screening rare variants of these genes in patients from Brazil. Methods A total of 122 Brazilian severely obese patients (BMI ≥ 35 kg/m 2 ) were screened for the coding regions of LEP , MRAP2 and POMC by Sanger sequencing. All patients are candidates to the bariatric surgery. Clinical characteristics were described in patients with novel and/or potentially pathogenic variants. Results Sixteen different variants were identified in these genes, of which two were novel. Among them, one previous variant with potentially deleterious effect in MRAP2 (p.Arg125Cys) was found. In addition, two heterozygous mutations in POMC (p.Phe87Leu and p.Arg90Leu) were predicted to impair protein function. We also observed a POMC homozygous 9 bp insertion (p.Gly99_Ala100insSerSerGly) in three patients. No pathogenic variant was observed in LEP . Conclusion Our study described for the first time the prevalence of rare potentially pathogenic MRAP2 and POMC variants in a cohort of Brazilian severely obese adults. Level of evidence Level V, cross-sectional descriptive study.

The aim of this study was to sequence the coding region of the gene in a Brazilian cohort with clinical manifestations of monogenic diabetes. This study included 31 patients with autosomal dominant history of diabetes, age at diagnosis ≤40 years, BMI <30 kg/m , and no mutations in or , and . Screening of the coding region was performed by Sanger sequencing. In silico algorithms were used to assess the potential impact of amino acid substitutions on protein structure and function. Additionally, PAX4-MODY family members and 158 control subjects without diabetes were analyzed for the identified mutation. The molecular analysis of has detected one missense mutation, p.Arg164Gln (c.491G>A), segregating with diabetes in a large Brazilian family. The mutation was absent among the control group. The index case is a woman diagnosed at 32 years of age with polyneuropathy and treated with insulin. She did not present diabetic renal disease or retinopathy. Family members with the p.Arg164Gln mutation have a heterogeneous clinical manifestation and treatment response, with age at diagnosis ranging from 24 years to 50 years. To the best of our knowledge, this is the first study to report a PAX4-MODY family in Brazil. The age of PAX4-MODY diagnosis in the Brazilian family seems to be higher than the classical criteria for MODY. Our results reinforce the importance of screening large monogenic diabetes families for the understanding of the clinical manifestations of rare forms of diabetes for the specific and personalized treatment.

Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and perinatal morbimortality. Dietetic, phenotypic, and genotypic factors influencing HDP were analyzed during a nutrigenetic trial in Rio de Janeiro, Brazil (2016–2020). Pregnant women with pregestational diabetes mellitus (n = 70) were randomly assigned to a traditional or DASH diet group. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured during prenatal visits and HDP were diagnosed using international criteria. Phenotypic data were obtained from medical records and personal interviews. Genotyping for FTO and ADRB2 polymorphisms used RT-PCR. Linear mixed-effect models and time-to-event analyses were performed. The variables with significant effect on the risk for progression to HDP were: black skin color (adjusted hazard ratio [aHR] 8.63, p = 0.01), preeclampsia in previous pregnancy (aHR 11.66, p < 0.01), SBP ≥ 114 mmHg in the third trimester (aHR 5.56, p 0.04), DBP ≥ 70 mmHg in the first trimester (aHR 70.15, p = 0.03), mean blood pressure > 100 mmHg (aHR 18.42, p = 0.03), and HbA1c ≥ 6.41% in the third trimester (aHR 4.76, p = 0.03). Dietetic and genotypic features had no significant effect on the outcome, although there was limited statistical power to test both.

Background MODY‐NEUROD1 is a rare form of monogenic diabetes caused by mutations in Neuronal differentiation 1 (NEUROD1). Until now, only a few cases of MODY‐NEUROD1 have been reported worldwide and the real contribution of mutations in NEUROD1 in monogenic diabetes and its clinical impact remain unclear. Methods Genomic DNA was isolated from peripheral blood lymphocytes of 25 unrelated Brazilians patients with clinical characteristics suggestive of monogenic diabetes and the screening of the entire coding region of NEUROD1 was performed by Sanger sequencing. Results We identified one novel frameshift deletion (p.Phe256Leufs*2) in NEUROD1 segregating in an autosomal dominant inheritance fashion. Almost 20 years after the first report of NEUROD1‐MODY, only a few families in Europe and Asia had shown mutations in NEUROD1 as the cause of monogenic diabetes. Conclusion To our knowledge, we described the first case of NEUROD1‐MODY in a Latin American family. In the present study, one novel frameshift deletion (p.Phe256Leufs*2) was identified in NEUROD1 segregating in a diabetic family. This is the first case of MODY‐NEUROD1 reported in Latin America.

gene ( ) is an important regulator of food intake, body weight, and blood pressure. Mutations in are associated with the most common form of nonsyndromic monogenic obesity. variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the gene in a Brazilian cohort of severely obese adults and to investigate the phenotype-genotype correlation within variant carriers. This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0-11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12-21 years). The entire coding region of gene was screened by Sanger sequencing. As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of . It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying variants had higher median of waist-hip ratio when compared to noncarriers ( =0.048). These missense variants were also associated with hypertension ( =0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers ( =0.020 and =0.065, respectively). Val103Ile was also associated with hypertension ( =0.003). This study showed the prevalence of variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of on body fat distribution and blood pressure.