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1.
Eat Weight Disord ; 27(8): 3665-3674, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36436143

RESUMO

PURPOSE: SH2B1 gene encodes an important adaptor protein to receptor tyrosine kinases or cytokine receptors associated with Janus kinases. This gene has been associated with the structural and functional modulation of neurons and other cells, and impacts on energy and glucose homeostasis. Several studies suggested that alterations in this gene are strong candidates for the development of obesity. However, only a few studies have screened SH2B1 point variants in individuals with obesity. Therefore, the aim of this study was to investigate the prevalence of SH2B1 variants in a Brazilian cohort of patients with severe obesity and candidates to bariatric surgery. METHODS: The cohort comprised 122 individuals with severe obesity, who developed this phenotype during childhood. As controls, 100 normal-weight individuals were included. The coding region of SH2B1 gene was screened by Sanger sequencing. RESULTS: A total of eight variants were identified in SH2B1, of which p.(Val345Met) and p.(Arg630Gln) variants were rare and predicted as potentially pathogenic by the in the silico algorithms used in this study. The p.(Val345Met) was not found in either the control group or in publicly available databases. This variant was identified in a female patient with severe obesity, metabolic syndrome and hyperglycemia. The p.(Arg630Gln) was also absent in our control group, but it was reported in gnomAD with an extremely low frequency. This variant was observed in a female patient with morbid obesity, metabolic syndrome, hypertension and severe binge-eating disorder. CONCLUSION: Our study reported for the first time two rare and potentially pathogenic variants in Brazilian patients with severe obesity. Further functional studies will be necessary to confirm and elucidate the impact of these variants on SH2B1 protein function and stability, and their impact on energetic metabolism. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.


Assuntos
Síndrome Metabólica , Obesidade Mórbida , Humanos , Feminino , Obesidade Mórbida/genética , Brasil , Estudos Transversais , Proteínas Adaptadoras de Transdução de Sinal
2.
Eat Weight Disord ; 26(4): 1079-1087, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32918257

RESUMO

PURPOSE: The rs17782313 variant of the MC4R gene plays an important role in the obesity phenotype. Studies that evaluate environmental factors and genetic variants associated with obesity may represent a great advance in understanding the development of this disease. This work seeks to assess the association of the polymorphism of MC4R rs17782313 on plasma parameters, including leptin, ghrelin, tumor necrosis factor (TNFα) and interleukin 6 (IL6), and on the eating behaviors of morbidly obese women. METHODS: 70 adult women with BMI between 40 and 60 kg/m2 were recruited. Laboratory and anthropometric data were recorded. Using a visual analog scale (VAS), the feelings of hunger and satiety were evaluated. The presence or absence of binge eating was evaluated through the Binge Eating Scale (BES) questionnaire. Habitual food intake was analyzed using 3-day dietary records. TaqMan® assays were conducted using real-time PCR to assess genotype polymorphism variants from peripheral blood DNA. RESULTS: This study found that female patients with the MC4R rs17782313 polymorphism had high levels of ghrelin and reduced levels of IL6 in the postprandial period. We observed a higher prevalence of severe binge eating in more than 50% of women with at least one risk allele. CONCLUSION: Our hypothesis is that the MC4R rs17782313 polymorphism may influence the release of ghrelin, even without being associated with feelings of hunger and satiety. More than half of women with this polymorphism exhibited severe binge eating. LEVEL OF EVIDENCE: Level III: case-control analytic study.


Assuntos
Leptina , Obesidade Mórbida , Adulto , Índice de Massa Corporal , Ingestão de Alimentos/genética , Comportamento Alimentar , Feminino , Grelina/genética , Humanos , Interleucina-6/genética , Leptina/genética , Obesidade Mórbida/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/genética , Fator de Necrose Tumoral alfa
3.
Eat Weight Disord ; 26(5): 1399-1408, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32578125

RESUMO

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/m2) 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.


Assuntos
Obesidade Mórbida , Pró-Opiomelanocortina , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Brasil , Estudos Transversais , Humanos , Leptina , Obesidade Mórbida/genética , Pró-Opiomelanocortina/genética , Pró-Proteína Convertases , Receptor Tipo 4 de Melanocortina/genética
4.
Front Genet ; 15: 1363417, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38841722

RESUMO

Introduction: Obesity is a multifactorial disease associated with the development of many comorbidities. This disease is associated with several metabolic alterations; however, it has been shown that some individuals with obesity do not exhibit metabolic syndrome. Adipose tissue neutralizes the detrimental effects of circulating fatty acids, ectopic deposition, and inflammation, among others, through its esterification into neutral lipids that are stored in the adipocyte. However, when the adipocyte is overloaded, i.e., its expansion capacity is exceeded, this protection is lost, resulting in fatty acid toxicity with ectopic fat accumulation in peripheral tissues and inflammation. In this line, this study aimed to investigate whether polymorphisms in genes that control adipose tissue fat storage capacity are potential biomarkers for severe obesity susceptibility and also metabolic complications. Methods: This study enrolled 305 individuals with severe obesity (cases, BMI≥35 kg/m2) and 196 individuals with normal weight (controls, 18.5≤BMI≤24.9 kg/m2). Demographic, anthropometric, biochemical, and blood pressure variables were collected from the participants. Plasma levels of leptin, resistin, MCP1, and PAI1 were measured by Bio-Plex 200 Multiplexing Analyzer System. Genomic DNA was extracted and variants in DBC1 (rs17060940), SIRT1 (rs7895833 and rs1467568), UCP2 (rs660339), PPARG (rs1801282) and ADRB2 (rs1042713 and rs1042714) genes were genotyped by PCR allelic discrimination using TaqMan® assays. Results: Our findings indicated that SIRT1 rs7895833 polymorphism was a risk factor for severe obesity development in the overdominant model. SIRT1 rs1467568 and UCP2 rs660339 were associated with anthropometric traits. SIRT1 rs1467568 G allele was related to lower medians of body adipose index and hip circumference, while the UCP2 rs660339 AA genotype was associate with increased body mass index. Additionally, DBC1 rs17060940 influenced glycated hemoglobin. Regarding metabolic alterations, 27% of individuals with obesity presented balanced metabolic status in our cohort. Furthermore, SIRT1 rs1467568 AG genotype increased 2.5 times the risk of developing metabolic alterations. No statistically significant results were observed with Peroxisome Proliferator-Activated Receptor Gama and ADRB2 polymorphisms. Discussion/Conclusion: This study revealed that SIRT1 rs7895833 and rs1467568 are potential biomarkers for severe obesity susceptibility and the development of unbalanced metabolic status in obesity, respectively. UCP2 rs660339 and DBC1 rs17060940 also showed a significant role in obesity related-traits.

5.
Genes (Basel) ; 14(7)2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37510350

RESUMO

Classically, genetic association studies have attempted to assess genetic polymorphisms related to human physiology and physical performance. However, the heterogeneity of some findings drives the research to replicate, validate, and confirmation as essential aspects for ensuring their applicability in sports sciences. Genetic distance matrix and molecular variance analyses may offer an alternative approach to comparing athletes' genomes with those from public databases. Thus, we performed a complete sequencing of 44 genomes from male Brazilian first-division soccer players under 20 years of age (U20_BFDSC). The performance-related SNP genotypes were obtained from players and from the "1000 Genomes" database (European, African, American, East Asian, and South Asian). Surprisingly, U20_BFDSC performance-related genotypes had significantly larger FST levels (p < 0.00001) than African populations, although studies using ancestry markers have shown an important similarity between Brazilian and African populations (12-24%). U20_BFDSC were genetically similar to professional athletes, showing the intense genetic selection pressure likely to occur before this maturation stage. Our study highlighted that performance-related genes might undergo selective pressure due to physical performance and environmental, cognitive, and sociocultural factors. This replicative study suggests that molecular variance and Wright's statistics can yield novel conclusions in exercise science.


Assuntos
Desempenho Atlético , Futebol , Humanos , Masculino , Adolescente , Futebol/fisiologia , Brasil , Desempenho Atlético/fisiologia , Atletas , Exercício Físico
6.
Life (Basel) ; 13(5)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37240750

RESUMO

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.

7.
Nutr Cancer ; 64(4): 569-79, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22483364

RESUMO

A fatty diet is regarded as one of the most important risk factors related to the etiology of colorectal cancer, and this effect is linked to the quantity and principal types of fatty acids consumed. In this study, the chemopreventive effects of different oils on rats were investigated. Forty Wistar rats received 1,2-dimetilhidrazine (DMH) and were divided into 4 groups fed normal lipid diets to which 4% olive, fish, flaxseed, or soybean oils (control) were added. The group fed with fish oil presented higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid in hepatic tissue and greater levels of linolenic acid and EPA in adipose tissue compared to the other treatments. In the proximal portion of the colon, lower levels of aberrant crypt foci were found in the fish and flaxseed oil groups; however, this behavior was not observed in the middle and distal regions. Via a benchmarking method, the fish oil group showed a greater transforming growth factor ß expression and lower interleukin-8 expression in relation to the other treatments. Fish oil in a normal lipid diet demonstrated a limited protective effect on the colonic precancerous mucosa in carcinogen-treated rodents, whereas it had a beneficial effect on inflammatory modulation.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Óleos de Peixe/farmacologia , Interleucina-8/sangue , Interleucina-8/efeitos dos fármacos , 1,2-Dimetilidrazina/toxicidade , Animais , Carcinógenos/toxicidade , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Masculino , Ratos , Ratos Wistar , Ácido alfa-Linolênico/farmacologia
8.
Nutrients ; 14(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35268025

RESUMO

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).


Assuntos
Diabetes Mellitus , Ganho de Peso na Gestação , Gravidez em Diabéticas , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Feminino , Ganho de Peso na Gestação/genética , Humanos , Recém-Nascido , Nutrigenômica , Polimorfismo Genético , Gravidez , Gestantes , Receptores Adrenérgicos beta 2/genética , Fatores de Risco , Estados Unidos , Aumento de Peso/genética
9.
Front Endocrinol (Lausanne) ; 13: 827325, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35592779

RESUMO

Monogenic forms of diabetes mellitus may affect a significant number of patients of this disease, and it is an important molecular cause to be investigated. However, studies of the genetic causes of monogenic diabetes, especially in populations with mixed ethnic backgrounds, such as the one in Brazil, are scarce. The aim of this study was to screen several genes associated with monogenic diabetes in fifty-seven Brazilian patients with recurrence of the disease in their families and thirty-four relatives. Inclusion criteria were: Age of onset ≤ 40 years old, BMI < 30 kg/m², at least two affected generations and negative anti-GAD and anti-IA2 antibodies. MODY genes HNF4A, GCK, HNF1A, HNF1B, NEUROD1, KLF11, PAX4, INS, KCNJ11, and MT-TL1 were sequenced by Sanger sequencing. We identified a total of 20 patients with variants, 13 GCK-MODY, four HNF1A-MODY, and one variant in each of the following genes, HNF4A, HNF1B and MT-TL1. Segregation analysis was performed in 13 families. Four variants were novel, two in GCK (p.(Met115Val) [c.343A>G] and p.(Asp365GlufsTer95) [c.1094_1095insGCGA]) and two in HNF1A (p.(Tyr163Ter) [c.489C>G] and p.(Val380CysfsTer39) [c.1136_1137insC]). Here we highlight the importance of screening for monogenic diabetes in admixed populations.


Assuntos
Diabetes Mellitus Tipo 2 , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Brasil/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Humanos , Mutação
10.
Urol Case Rep ; 34: 101479, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33209586

RESUMO

Schistosomose mansoni is an endemic disease in Brazil. It rarely affects the central nervous system, particularly in children. We report the case of a child that presented with an acute spinal cord compression condition, resulting from a mass that proved to be a granuloma caused by a Schistosoma mansoni infection. Proper treatment had no effect on the regression of urological symptoms and the child had to undergo a Mitrofanoff principle.

11.
Eur J Med Genet ; 64(5): 104194, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33746035

RESUMO

Maturity-Onset Diabetes of the Young type 4 is a rare form of diabetes mellitus, caused by mutations in the PDX1 gene. However, only a few mutations in this gene have been associated as a cause of monogenic diabetes up to date. It makes difficult to create a clinical manifestation profile of this disease and, consequently, to improve the therapeutic management for these patients. Here we report a normal weight woman, diagnosed with diabetes mellitus at 27 years old, during her first pregnancy. At the time of the recruitment, she was 40 years old and had a body mass index of 23.9 kg/m2, glycated hemoglobin level of 9.6%, and fasting plasma glucose (FPG) of 254 mg/dL. She presented no diabetic complications and she was being treated with insulin. She reported a family history of diabetes mellitus characteristic of an autosomal dominant mode of inheritance. Molecular analysis of the PDX1 gene revealed the missense variant c.532G > A (p.(Glu178Lys)) segregating from the patient to her son, reported as diabetic. It was absent in her healthy daughter. The c.532G > A seems to be a rare variant, absent in human variants databases, and among 86 normoglycemic controls. Eight in silico algorithms classified this variant as probably pathogenic. Additionally, analysis of the evolutionary conservation showed the glutamic acid in the position 178 of PDX-1 protein as conserved among several species. Our findings reinforce the importance of screening rare MODY genes among families with suspicion of monogenic diabetes to help better understand the clinical manifestations of this disease.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteínas de Homeodomínio/genética , Transativadores/genética , Adulto , Idoso , Sequência Conservada , Diabetes Mellitus Tipo 2/patologia , Feminino , Proteínas de Homeodomínio/química , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Transativadores/química
12.
Front Endocrinol (Lausanne) ; 12: 722441, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504472

RESUMO

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.


Assuntos
Leptina/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/genética , Metabolismo Energético/genética , Terapia de Reposição Hormonal , Humanos , Leptina/deficiência , Leptina/genética , Mutação , Obesidade/congênito , Fenótipo
13.
Diabetes Metab Syndr Obes ; 14: 11-22, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33442278

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a pro-survival factor in the brain that also regulates energy balance. BDNF loss-of-function point mutations are responsible for haploinsufficiency, causing severe early-onset obesity. Up to date, only a few studies have sequenced this gene to search for rare mutations related to obesity. In this study, we aimed to investigate the prevalence of BDNF variants in a cohort of adults with severe obesity from Brazil. MATERIAL AND METHODS: This study comprised 201 adults with severe obesity (BMI ≥ 35.0 kg/m2) with onset during childhood- or adolescence/youth. As controls, 73 subjects with normal weight (18.5 ≤ BMI ≤ 24.9 kg/m2) were selected. The exclusion criteria were pregnancy, lactation, the use of medication to lose or gain weight, and the presence of symptoms suggestive of syndromic obesity (only for the case group). The coding region of the BDNF gene was screened by Sanger sequencing. Demographic, anthropometric, and blood pressure parameters were obtained from the participants as well as serum hormone and cytokines concentrations and biochemical values. RESULTS: As a result, three missense variants [p.(Thr2Ile), p.(Val66Met), and p.(Arg209Gln)] and four synonymous variants (p.Leu107=, p.Thr149=, p.Ala150=, and p.Ser213=) were identified. The p.(Arg209Gln) was predicted as pathogenic by all in silico algorithms used and was not observed in the control group. The individuals carrying the p.(Val66Met) mutated allele had higher waist circumference, HDL-cholesterol and MCP1 levels, and reduced risk of developing metabolic syndrome. CONCLUSION: We observed that the common BDNF p.(Val66Met) variant has influenced waist circumference, HDL-cholesterol, and MCP1 levels. This polymorphism has also a protective effect on metabolic syndrome susceptibility. Additionally, we described for the first time a rare potentially pathogenic BDNF variant in a Brazilian patient with severe obesity and childhood-onset.

14.
Nutrition ; 71: 110618, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31881507

RESUMO

OBJECTIVE: The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes, serum 25-hydroxyvitamin D [25(OH)D] concentrations, and leukocyte telomere length (LTL) in Brazilian adults. METHODS: The study population comprised 461 participants (33-79 y of age; 51% women) from the Pró-Saúde Study, a cohort of civil servants at a university campus in Rio de Janeiro, Brazil. LTL, genotypes of vitamin D-related SNPs (rs12785878, rs10741657, rs6013897, and rs2282679), and serum 25(OH)D concentrations were determined cross-sectionally. Differences in age- and sex-adjusted LTL means by categories of genotypes and 25(OH)D serum concentrations were evaluated. LTL associations with genotypes and 25(OH)D were investigated using multiple linear regression models adjusted for sociodemographic characteristics and markers of health behavior. RESULTS: Participants with CC genotype (rs2282679) had shorter age- and sex-adjusted mean LTL than those with AC and AA genotypes (mean ± SE: 0.51 ± 0.03, 0.58 ± 0.01 and 0.5 ± 0.01, respectively, P < 0.05). In adjusted analyses, the CC genotype (rs2282679) was inversely associated with LTL (ß = -0.061; 95% confidence interval, -0.120 to -0.001). Other vitamin D-related SNPs and serum 25(OH)D concentrations were not associated with LTL. CONCLUSIONS: Genetic variations in the gene encoding vitamin D binding protein (GC - rs2282679) were associated with LTL, suggesting an influence of vitamin D status on telomere length that may start early in life.


Assuntos
Leucócitos/fisiologia , Estado Nutricional/genética , Polimorfismo de Nucleotídeo Único/genética , Telômero/genética , Proteína de Ligação a Vitamina D/genética , Adulto , Idoso , Brasil , Estudos Transversais , Feminino , Genótipo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Homeostase do Telômero , Vitamina D/análogos & derivados
15.
Diabetes Metab Syndr Obes ; 13: 2623-2631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801813

RESUMO

PURPOSE: The aim of this study was to sequence the coding region of the PAX4 gene in a Brazilian cohort with clinical manifestations of monogenic diabetes. PATIENTS AND METHODS: This study included 31 patients with autosomal dominant history of diabetes, age at diagnosis ≤40 years, BMI <30 kg/m2, and no mutations in GCK or HNF1A, HNF4A, and HNF1B. Screening of the PAX4 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. RESULTS: The molecular analysis of PAX4 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 PAX4 p.Arg164Gln mutation have a heterogeneous clinical manifestation and treatment response, with age at diagnosis ranging from 24 years to 50 years. CONCLUSION: 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.

16.
Obes Facts ; 13(2): 130-143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32325455

RESUMO

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.


Assuntos
Adipócitos Marrons/fisiologia , Adipócitos/fisiologia , Transdiferenciação Celular/genética , Fibronectinas/genética , Obesidade Mórbida/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Polimorfismo de Nucleotídeo Único , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Transversais , Metabolismo Energético/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Mutação de Sentido Incorreto , Obesidade Mórbida/metabolismo , Obesidade Mórbida/fisiopatologia , Adulto Jovem
17.
Front Genet ; 11: 608840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362866

RESUMO

BACKGROUND: The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity. METHODS: This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m2, stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0-11 years), 19 patients in the adolescence/youth-onset group (12-21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject's DNA was assessed using automated Sanger sequencing. RESULTS: Significant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity. CONCLUSION: This study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.

18.
Mol Genet Genomic Med ; 7(12): e989, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31578821

RESUMO

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.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 2/genética , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Brasil/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Família , Feminino , Mutação da Fase de Leitura/genética , Testes Genéticos/métodos , Genoma Humano/genética , Humanos , América Latina/epidemiologia , Masculino , Mutação/genética , Linhagem , Análise de Sequência de DNA/métodos
19.
Diabetes Metab Syndr Obes ; 12: 667-684, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213864

RESUMO

Background: Obesity occurs due to the interaction between the genetic background and environmental factors, including an increased food intake and a sedentary lifestyle. Nowadays, it is clear that there is a specific circuit, called leptin-melanocortin pathway, which stimulates and suppresses food intake and energy expenditure. Therefore, the aim of this study was to evaluate the influence of genetic variants related to appetite regulation and energy expenditure on severe obesity susceptibility and metabolic phenotypes in a Brazilian cohort. Material and methods: A total of 490 participants were selected (298 severely obese subjects and 192 normal-weight individuals). Genomic DNA was extracted and polymorphisms in protein related to agouti (AGRP; rs5030980), ghrelin (GHRL; rs696217), neuropeptide Y (NPY; rs535870237), melanocortin 4 receptor (MC4R; rs17782313), brain-derived neurotrophic factor (BDNF; rs4074134) and fat mass and obesity-associated (FTO; rs9939609) genes were genotyped using TaqMan® probes. Demographic, anthropometric, biochemical and blood pressure parameters were obtained from the participants. Results: Our results showed that FTO rs9939609 was associated with severe obesity susceptibility. This polymorphism was also related to body weight, body mass index (BMI), waist to weight ratio (WWR) and inverted BMI. Individuals carrying the mutant allele (A) showed higher levels of BMI as well as lower values of WWR and inverted BMI. Conclusion: This study showed that FTO rs9939609 polymorphism plays a significant role in predisposing severe obesity in a Brazilian population.

20.
Mol Genet Genomic Med ; 7(7): e00645, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31199594

RESUMO

BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). There are over 2000 different pathogenic and non-pathogenic variants described in association with a broad clinical heterogeneity. The most common types of mutations in this gene are single nucleotide substitutions or small deletions and insertions. However, large rearrangements, such as large duplications or deletions, are also a possible cause of CF; these variations are rarely tested in routine screenings, and much of them remain unidentified in some populations, especially those with high ethnic heterogeneity. METHODS: The present study utilized the Multiplex Ligation-dependent Probe Amplification (MLPA) technique for the detection of duplications and deletions in 165 CF patients from the Rio de Janeiro State (Brazil), which after extensive mutational screening, still exhibited one or two unidentified CF alleles. RESULTS: Five patients with alterations in MLPA signals were detected. After validation, we identified three copy number variations, one large duplication (CFTRdup2-3) and two large deletions (CFTRdel25-26 and CFTRdel25-27-CTTNBP2). Two detected deletions were not validated. They were false positives caused by a small deletion of 18 base pairs (232del18) and a point mutation (S168L) in the probe binding site. CONCLUSION: Our results highlight the importance of screening for large rearrangements in CF cases with no or only one CFTR mutation defined.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/patologia , Pré-Escolar , Fibrose Cística/etnologia , Fibrose Cística/genética , DNA/química , DNA/genética , DNA/metabolismo , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Técnicas de Amplificação de Ácido Nucleico/métodos , Mutação Puntual
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