RESUMO
The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.
Assuntos
Cirurgia Bariátrica , Doenças Cardiovasculares , Criança , Feminino , Humanos , Adiposidade/genética , Obesidade/complicações , Índice de Massa Corporal , Telômero/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/complicaçõesRESUMO
BACKGROUND: Blueberries contain high levels of polyphenolic compounds with high in vitro antioxidant capacities. Their consumption has been associated with improved vascular and metabolic health. PURPOSE: The objective was to examine the effects of blueberry supplement consumption on metabolic syndrome (MetS) parameters and potential underlying mechanisms of action. METHODS: A randomized double-blind placebo-controlled intervention trial was conducted in adults at risk of developing MetS. Participants consumed 50 g daily of either a freeze-dried highbush blueberry powder (BBP) or a placebo powder for 8 weeks (n = 49). MetS phenotypes were assessed at weeks 0, 4 and 8. Fasting blood gene expression profiles and plasma metabolomic profiles were examined at baseline and week 8 to assess metabolic changes occurring in response to the BBP. A per-protocol analysis was used. RESULTS: A significant treatment effect was observed for plasma triglyceride levels that was no longer significant after further adjustments for age, sex, BMI and baseline values. In addition, the treatment*time interactions were non-significant therefore suggesting that compared with the placebo, BBP had no statistically significant effect on body weight, blood pressure, fasting plasma lipid, insulin and glucose levels, insulin resistance (or sensitivity) or glycated hemoglobin concentrations. There were significant changes in the expression of 49 genes and in the abundance of 35 metabolites following BBP consumption. Differentially regulated genes were clustered in immune-related pathways. CONCLUSION: An 8-week BBP intervention did not significantly improve traditional markers of cardiometabolic health in adults at risk of developing MetS. However, changes in gene expression and metabolite abundance suggest that clinically significant cardiometabolic changes could take longer than 8 weeks to present and/or could result from whole blueberry consumption or a higher dosage. BBP may also have an effect on factors such as immunity even within a shorter 8-week timeframe. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT03266055 , 2017.
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The search for bioactive compounds from enzymatic hydrolysates has increased in the last few decades. Fish by-products have been shown to be rich in these valuable molecules; for instance, herring milt is a complex matrix composed of lipids, nucleotides, minerals, and proteins. However, limited information is available on the potential health benefits of this by-product. In this context, three industrial products containing herring milt hydrolysate (HMH) were tested in both animal and cellular models to measure their effects on obesity-related metabolic disorders. Male C57Bl/6J mice were fed either a control chow diet or a high-fat high-sucrose (HFHS) diet for 8 weeks and received either the vehicle (water) or one of the three HMH products (HMH1, HMH2, and HMH3) at a dose of 208.8 mg/kg (representing 1 g/day for a human) by daily oral gavage. The impact of HMH treatments on insulin and glucose tolerance, lipid homeostasis, liver gene expression, and the gut microbiota profile was studied. In parallel, the effects of HMH on glucose uptake and inflammation were studied in L6 myocytes and J774 macrophages, respectively. In vivo, daily treatment with HMH2 and HMH3 improved early time point glycemia during the oral glucose tolerance test (OGTT) induced by the HFHS diet, without changes in weight gain and insulin secretion. Interestingly, we also observed that HMH2 consumption partially prevented a lower abundance of Lactobacillus species in the gut microbiota of HFHS diet-fed animals. In addition to this, modulations of gene expression in the liver, such as the upregulation of sucrose nonfermenting AMPK-related kinase (SNARK), were reported for the first time in mice treated with HMH products. While HMH2 and HMH3 inhibited inducible nitric oxide synthase (iNOS) induction in J774 macrophages, glucose uptake was not modified in L6 muscle cells. These results indicate that milt herring hydrolysates reduce some metabolic and inflammatory alterations in cellular and animal models, suggesting a possible novel marine ingredient to help fight against obesity-related immunometabolic disorders.
Assuntos
Produtos Pesqueiros , Intolerância à Glucose/dietoterapia , Inflamação , Macrófagos/imunologia , Obesidade/complicações , Animais , Glicemia/metabolismo , Linhagem Celular , Dieta da Carga de Carboidratos , Dieta Hiperlipídica , Sacarose Alimentar/administração & dosagem , Microbioma Gastrointestinal , Glucose/metabolismo , Intolerância à Glucose/etiologia , Teste de Tolerância a Glucose , Insulina/metabolismo , Fígado/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Musculares/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , RNA-SeqRESUMO
BACKGROUND: There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity. RESULTS: A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath's epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10-12) and VAT (r = 0.80, p = 1.1 × 10-12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3 years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04-1.48; p = 0.03). CONCLUSIONS: Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.
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Metilação de DNA , Gordura Intra-Abdominal/química , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Desvio Biliopancreático , Índice de Massa Corporal , Epigênese Genética , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/cirurgia , Adulto JovemRESUMO
Fish contains high quality proteins and essential nutrients including 25-hydroxyvitamin D (25(OH)D). Fish peptide consumption can lower cardiovascular disease (CVD) risk factors, and studies have shown an association between 25(OH)D deficiency, CVD and CVD risk factors, such as diabetes. This study investigated acute effects of a single dose of cholecalciferol (VitD3), bonito fish peptide hydrolysate (BPH), or a combination of both on CVD risk factors and whole blood gene expression levels. A randomized, crossover, placebo controlled trial was conducted in 22 adults. They ingested, in random order and at 7-day intervals, 1000 IU of VitD3, 3 g of BPH, a combination of both, or a placebo. A 180 min oral glucose tolerance test was performed. Differences in whole-genome expression levels after versus before each supplementation were computed for 18 subjects. We observed that 16, 1 and 5 transcripts were differentially expressed post- vs. pre-ingestion for VitD3, BPH or VitD3 + BPH treatments, respectively. VitD3-containing treatments affected the expression of the solute carrier family 25 member 20 (SLC25A20) gene involved in fatty acid oxidation, various transcription factors and genes related to glucose metabolism. These results suggest that VitD3 rapidly modulates genes related to CVD risk factors in blood while BPH seems to moderately modulate gene expression levels.
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Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos/administração & dosagem , Vitamina D/administração & dosagem , Adulto , Idoso , Animais , Glicemia/metabolismo , Peptídeo C/sangue , Estudos de Coortes , Feminino , Peixes , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Vitamina D/farmacologia , Adulto JovemRESUMO
BACKGROUND: The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS: Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and two polygenic risk scores were constructed with 186 and 11 (PRS186 and PRS11) single nucleotide polymorphisms previously associated with body mass index (BMI). RESULTS: The accuracy of the %EBWL logistic prediction model - including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism (AUCadj = 0.867) - significantly increased after the inclusion of PRS186 (ΔAUCadj = 0.021; 95% CI of the difference [95% CIdiff] = 0.005-0.038) but not PRS11 (ΔAUCadj= 0.008; 95% CIdiff= -0.003-0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS186 (-2 log-likelihood = 12.3; P = 0.002) and PRS11 (-2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS186 (ß = -0.003; P = 0.008) and PRS11 (ß = -0.008; P = 0.03). The inclusion of PRS186 and PRS11 in the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION: These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity. FUNDING: Heart and Stroke Foundation of Canada (G-17-0016627) and Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health (no. 950-231-580).
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Cirurgia Bariátrica/métodos , Desvio Biliopancreático/métodos , Herança Multifatorial/genética , Obesidade Mórbida/cirurgia , Redução de Peso , Adulto , Canadá , Análise Custo-Benefício , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade Mórbida/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: An appropriate intake of omega-3 (n-3) fatty acids (FAs) such as eicosapentaenoic and docosahexaenoic acid (EPA/DHA) from marine sources is known to have anti-inflammatory effects. However, molecular mechanisms underlying their beneficial effects on health are not fully understood. The aim of the present study was to characterize gene expression profiles of THP-1 macrophages, incubated in either EPA or DHA and stimulated with lipopolysaccharide (LPS), a pro-inflammatory agent. Methods: THP-1 macrophages were incubated into 10, 50 and 75 µM of EPA or DHA for 24 h, and 100 nM of LPS was added to the culture media for 18 h. Total mRNA was extracted and gene expression examined by microarray analysis using Illumina Human HT-12 expression beadchips (Illumina). Results: Pathway analysis revealed that EPA and DHA regulate genes involved in cell cycle regulation, apoptosis, immune response and inflammation, oxidative stress and cancer pathways in a differential and dose-dependent manner. Conclusions: EPA and DHA appear to exert differential effects on gene expression in THP-1 macrophages. Specific effects of n-3 FAs on gene expression levels are also dose-dependent.
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Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transcriptoma/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacologia , Humanos , Inflamação/metabolismo , Células THP-1RESUMO
A genome-wide association study (GWAS) by our group identified loci associated with the plasma triglyceride (TG) response to ω-3 fatty acid (FA) supplementation in IQCJ, NXPH1, PHF17 and MYB. Our aim is to investigate potential mechanisms underlying the associations between single nucleotide polymorphisms (SNPs) in the four genes and TG levels following ω-3 FA supplementation. 208 subjects received 3 g/day of ω-3 FA (1.9-2.2 g of EPA and 1.1 g of docosahexaenoic acid (DHA)) for six weeks. Plasma TG were measured before and after the intervention. 67 SNPs were selected to increase the density of markers near GWAS hits. Genome-wide expression and methylation analyses were conducted on respectively 30 and 35 participants' blood sample together with in silico analyses. Two SNPs of IQCJ showed different affinities to splice sites depending on alleles. Expression levels were influenced by genotype for one SNP in NXPH1 and one in MYB. Associations between 12 tagged SNPs of IQCJ, 26 of NXPH1, seven of PHF17 and four of MYB and gene-specific CpG site methylation levels were found. The response of plasma TG to ω-3 FA supplementation may be modulated by the effect of DNA methylation on expression levels of genes revealed by GWAS.
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Regulação da Expressão Gênica , Glicoproteínas/genética , Proteínas de Homeodomínio/genética , Neuropeptídeos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Triglicerídeos/sangue , Proteínas Supressoras de Tumor/genética , Adulto , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Glicoproteínas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Neuropeptídeos/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND: A recent genome-wide association study (GWAS) by our group identified 13 loci associated with the plasma triglyceride (TG) response to omega-3 (n-3) fatty acid (FA) supplementation. This study aimed to test whether single-nucleotide polymorphisms (SNPs) within the IQCJ, NXPH1, PHF17 and MYB genes are associated with the plasma TG response to an n-3 FA supplementation. METHODS: A total of 208 subjects followed a 6-week n-3 FA supplementation of 5 g/day of fish oil (1.9-2.2 g of eicosapentaenoic acid and 1.1 g of docosahexaenoic acid). Measurements of plasma lipids were made before and after the supplementation. Sixty-seven tagged SNPs were selected to increase the density of markers near GWAS hits. RESULTS: In a repeated model, independent effects of the genotype and the gene-supplementation interaction were associated with plasma TG. Genotype effects were observed with two SNPs of NXPH1, and gene-diet interactions were observed with ten SNPs of IQCJ, four SNPs of NXPH1 and three SNPs of MYB. Positive and negative responders showed different genotype frequencies with nine SNPs of IQCJ, two SNPs of NXPH1 and two SNPs of MYB. CONCLUSION: Fine mapping in GWAS-associated loci allowed the identification of SNPs partly explaining the large interindividual variability observed in plasma TG levels in response to an n-3 FA supplementation.
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Proteínas de Ligação a Calmodulina/genética , Ácidos Graxos Ômega-3/administração & dosagem , Genes myb , Glicoproteínas/genética , Proteínas de Homeodomínio/genética , Neuropeptídeos/genética , Triglicerídeos/sangue , Proteínas Supressoras de Tumor/genética , Adulto , Suplementos Nutricionais , Feminino , Óleos de Peixe/administração & dosagem , Estudo de Associação Genômica Ampla , Humanos , Masculino , Nutrigenômica , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Uncontrolled inflammation participates in the development of inflammatory diseases. Beneficial effects of polyunsaturated fatty acids belonging to the n-3 family such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on inflammation have been reported. The present study investigates the basal effects of EPA, DHA and a mixture EPA + DHA on the expression of 10 genes (AKT1, MAPK, NFKB, TNFA, IL1Β, MCP1, ALOX5, PTGS2, MGST1 and NOS2) related to inflammation in unstimulated cultured THP1 macrophages. Cells were incubated for 24 h with n-3 PUFAs (50 µM and 10 µM EPA, DHA, EPA + DHA). Expression levels of inflammatory genes were analyzed by real-time PCR. RESULTS: 50 µM, 10 µM EPA and 50 µM EPA + DHA decreased the expression of genes involved in the NF-κB pathway (MAPK, AKT1, and NFKB). Treatment with 50 µM, 10 µM EPA, 50 µM DHA and EPA + DHA decreased expression levels of cytokines genes IL1Β and MCP1. TNFA expression was decreased by 50 µM, 10 µM of EPA, DHA and with 50 µM EPA + DHA. Two genes involved in the fatty acid metabolism (PTGS2 and ALOX5) were also modulated by the n-3 FAs. 50 µM of DHA and EPA + DHA inhibited PTGS2 expression when the two concentrations of EPA, 50 µM DHA and EPA + DHA inhibited ALOX5 expression. Finally, the effects of n-3 FAs were studied among genes involved in the oxidative stress. 50 µM of each fatty acid increased MGST1 expression. Both concentration of EPA and 50 µM DHA decreased NOS2 expression. CONCLUSION: EPA seems to be more effective than DHA and EPA + DHA in modulating expression levels of selected inflammatory genes. The concentration of 50 µM was globally more effective than 10 µM.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Macrófagos/efeitos dos fármacos , Linhagem Celular , Citocinas/genética , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Relação Dose-Resposta a Droga , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacologia , Glutationa Transferase/genética , Humanos , Macrófagos/fisiologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genéticaRESUMO
METHODS: Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis. RESULTS: Significant interactions (p ≤ 1.22 x 10(-12)) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways. CONCLUSION: We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism.
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Obesidade/genética , Obesidade/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Expressão Gênica , Genótipo , Humanos , Pessoa de Meia-Idade , Mães , Gravidez , Adulto JovemRESUMO
BACKGROUND: Maternal obesity, excess weight gain and overnutrition during pregnancy increase risks of obesity, type 2 diabetes mellitus, and cardiovascular disease in the offspring. Maternal biliopancreatic diversion is an effective treatment for severe obesity and is beneficial for offspring born after maternal surgery (AMS). These offspring exhibit lower severe obesity prevalence and improved cardiometabolic risk factors including inflammatory marker compared to siblings born before maternal surgery (BMS). OBJECTIVE: To assess relationships between maternal bariatric surgery and the methylation/expression of genes involved in the immune and inflammatory pathways. METHODS: A differential gene methylation analysis was conducted in a sibling cohort of 25 BMS and 25 AMS offspring from 20 mothers. Following differential gene expression analysis (23 BMS and 23 AMS), pathway analysis was conducted. Correlations between gene methylation/expression and circulating inflammatory markers were computed. RESULTS: Five immune and inflammatory pathways with significant overrepresentation of both differential gene methylation and expression were identified. In the IL-8 pathway, gene methylation correlated with both gene expression and plasma C-reactive protein levels. CONCLUSION: These results suggest that improvements in cardiometabolic risk markers in AMS compared to BMS offspring may be mediated through differential methylation of genes involved in immune and inflammatory pathways.
Assuntos
Cirurgia Bariátrica , Metilação de DNA , Mediadores da Inflamação , Inflamação/genética , Mães , Obesidade Mórbida/cirurgia , Adolescente , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Hereditariedade , Humanos , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/sangue , Interleucina-8/genética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/genética , Obesidade Mórbida/imunologia , Linhagem , Gravidez , Adulto JovemRESUMO
Obesity and overnutrition during pregnancy affect fetal programming of adult disease. Children born after maternal bariatric gastrointestinal bypass surgery (AMS) are less obese and exhibit improved cardiometabolic risk profiles carried into adulthood compared with siblings born before maternal surgery (BMS). This study was designed to analyze the impact of maternal weight loss surgery on methylation levels of genes involved in cardiometabolic pathways in BMS and AMS offspring. Differential methylation analysis between a sibling cohort of 25 BMS and 25 AMS (2-25 y-old) offspring from 20 mothers was conducted to identify biological functions and pathways potentially involved in the improved cardiometabolic profile found in AMS compared with BMS offspring. Links between gene methylation and expression levels were assessed by correlating genomic findings with plasma markers of insulin resistance (fasting insulin and homeostatic model of insulin resistance). A total of 5,698 genes were differentially methylated between BMS and AMS siblings, exhibiting a preponderance of glucoregulatory, inflammatory, and vascular disease genes. Statistically significant correlations between gene methylation levels and gene expression and plasma markers of insulin resistance were consistent with metabolic improvements in AMS offspring, reflected in genes involved in diabetes-related cardiometabolic pathways. This unique clinical study demonstrates that effective treatment of a maternal phenotype is durably detectable in the methylome and transcriptome of subsequent offspring.
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Metilação de DNA , Derivação Gástrica , Glucose/metabolismo , Obesidade/cirurgia , Complicações na Gravidez/cirurgia , Adulto , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Obesidade/complicações , Obesidade/genética , Gravidez , Complicações na Gravidez/genéticaRESUMO
The lipase A, lysosomal acid, cholesterol esterase enzyme (LIPA) is involved in the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) delivered to lysosomes. LIPA deficiency in human causes two distinct phenotypes characterized by intracellular storage of CE and derangements in the control of cholesterol production, namely the Wolman disease (WD) and the CE storage disease (CESD). To test the potential association of LIPA gene polymorphisms with obesity-related metabolic complications, promoter, exons, and intronic flanking regions of the LIPA gene were first sequenced in 25 individuals. From the 14 common polymorphisms identified, 12 tagging single-nucleotide polymorphisms (tSNPs) were genotyped in a cohort of 1,751 obese individuals. After adjustments for the effect of age, sex, diabetes, and medication, the C allele of SNP rs1051338 was associated with lower blood pressure (BP; systolic (SBP) P = 0.004; diastolic (DBP) P = 0.006). Three of the tested SNPs were associated with modifications of the plasma lipid profile. The G/G genotype of rs2071509 was associated with higher high-density lipoprotein cholesterol (HDL-C) levels (P = 0.009) and minor allele of rs1131706 was also associated with higher HDL-C (P = 0.004) and an association between rs3802656 and total cholesterol (total-C)/HDL-C ratio was identified (P = 0.04). These results thus suggest that LIPA polymorphisms contribute to the interindividual variability observed in obesity-related metabolic complications.
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Doenças Cardiovasculares/genética , Síndrome Metabólica/genética , Obesidade Mórbida/genética , Polimorfismo de Nucleotídeo Único , Esterol Esterase/genética , Triglicerídeos/sangue , Doença de Wolman/genética , Adulto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Obesidade Mórbida/sangue , Obesidade Mórbida/epidemiologia , Polimorfismo Genético , Quebeque/epidemiologia , Análise de Sequência de DNA , Esterol Esterase/sangue , Doença de Wolman/epidemiologia , Doença de WolmanRESUMO
Obese individuals are characterized by a chronic, low-grade inflammatory state. Increased levels of C-reactive protein (CRP), a marker of inflammation, have been observed in subjects with the metabolic syndrome. We have previously reported that genes encoding proteins involved in the anti-inflammatory and immune response are differentially expressed in visceral adipose tissue of obese men with or without the metabolic syndrome. Among these genes, the interferon-gamma-inducible protein 30 (IFI30), CD163 molecule (CD163), chemokine (C-X-C motif) ligand 9 (CXCL9) and thymic stromal lymphopoietin (TSLP), were selected for further genetic analyses. The aim of the study was to verify whether IFI30, CD163, CXCL9 and TSLP gene polymorphisms contribute to explain the inter-individual variability of the inflammatory profile of obesity assessed by plasma high-sensitivity CRP concentrations. A total of 1185 severely obese individuals were genotyped for single nucleotide polymorphisms (SNPs) covering most of the sequence-derived genetic variability at the IFI30, CD163, CXCL9 and TSLP gene loci (total of 27 SNPs). Following measurement of plasma CRP levels, subjects were divided into two groups, low vs. high using the median value of plasma CRP levels (8.31 mg/L) as a cutoff point. Genotype frequencies were compared between groups. Associations between genotypes and plasma CRP levels (continuous variable) were also tested after adjustments for age, sex, smoking and BMI. The rs11554159 and rs7125 IFI30 SNPs showed a significant difference in genotype frequencies (p<0.05) between subgroups of low vs. high plasma CRP levels (wild type homozygotes: rs11554159=47% vs. 55%, rs7125=31% vs. 24%, for low vs. high CRP groups, respectively). The association between rs11554159 and CRP levels as a continuous variable remained significant (p=0.004). Both carriers of the GA and AA genotypes demonstrated, on average, a 13% lower CRP levels in comparison with GG homozygotes. No association was observed between SNPs in the CD163, CXCL9 and TSLP genes and CRP levels. The IFI30 rs11554159 polymorphism could partially explain the inter-individual variability observed in the inflammatory profile associated with obesity.
Assuntos
Proteína C-Reativa/análise , Inflamação/genética , Obesidade Mórbida/genética , Polimorfismo de Nucleotídeo Único , Adulto , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/imunologia , Quimiocina CXCL9/genética , Citocinas/genética , Feminino , Genótipo , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Receptores de Superfície Celular/genética , Análise de Sequência de DNA , Linfopoietina do Estroma do TimoRESUMO
Inactivating mutations of the CHEK2 and STK11 genes are responsible for Li-Fraumeni and Peutz-Jeghers syndrome, respectively, both autosomal dominant syndromes associated with an increased risk of breast cancer. The PALB2/FANCN gene encodes a nuclear partner of BRCA2 and acts as a linker between BRCA1 and BRCA2. Monoallelic PALB2 truncating mutations were shown to confer higher risk of breast cancer. To evaluate the proportion of French Canadian non-BRCA1/BRCA2 families with high risk of breast cancer potentially harboring alterations in these three breast cancer susceptibility genes, the whole coding and flanking intronic sequences were analyzed in a series of 96 high-risk breast cancer individuals. Despite no PALB2 deleterious truncating mutations being identified, the c.1100delC breast-cancer-associated CHEK2 mutation and a STK11 mutation reported to be the causative mutation in a Peutz-Jeghers family were identified. This extensive analysis also led to the identification of several variants in these genes. Ascertainment of allele frequency of these variants in a cohort of 96 healthy unrelated women suggests a difference in allele frequency for two STK11 intronic variants. In addition, large genomic rearrangements in both STK11 and PALB2 were also examined. Our analysis led to the conclusion that CHEK2, STK11, and PALB2 mutations or large genomic rearrangements of either STK11 or PALB2 are rare, and do not contribute to a substantial fraction of breast cancer susceptibility in high-risk French Canadian breast cancer families.
Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Quinases Proteína-Quinases Ativadas por AMP , Adulto , Idoso , Canadá , Quinase do Ponto de Checagem 2 , Análise Mutacional de DNA , Família , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Humanos , Pessoa de Meia-Idade , Proteínas Nucleares/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Quebeque , Risco , Proteínas Supressoras de Tumor/fisiologiaRESUMO
Breast cancer is a heterogeneous disease displaying some degree of familial clustering. Highly penetrant breast cancer susceptibility genes represent approximately 20-25% of the familial aggregation of breast cancer. A significant proportion of this familial aggregation of breast cancer is thus yet to be explained by other breast cancer susceptibility genes. Given the high susceptibility conferred by the two major breast cancer predisposition genes, BRCA1 and BRCA2 and the implication of these genes in many key cellular processes, assessment of genes encoding BRCA1-interacting proteins as plausible breast cancer candidate genes is thus attractive. In this study, four genes encoding BRCA1-interacting proteins were analyzed in a cohort of 96 breast cancer individuals from high-risk non-BRCA1/BRCA2 French Canadian families. Although no deleterious truncating germline mutations or aberrant spliced mRNA species were identified, a total of 10, 4, 11 and 6 variants were found in the AURKA, BAP1, BARD1 and DHX9 genes, respectively. The allele frequency of each variant was further ascertained in a cohort of 98 healthy French Canadian unrelated women and a difference in allele frequency was observed for one BARD1 variant based on single-marker analysis. Haplotype estimation, haplotype blocks and tagging SNPs identification were then performed for each gene, providing a valuable tool for further searches of common disease-associated variants in these genes and therefore further analyses on these genes in larger cohorts is warranted in the search of low-to-moderate penetrance breast cancer susceptibility alleles.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Variação Genética , Proteínas de Neoplasias/genética , População Branca/genética , Aurora Quinase A , Aurora Quinases , Sequência de Bases , Canadá , Estudos de Casos e Controles , RNA Helicases DEAD-box/genética , Família , Feminino , França/etnologia , Haplótipos , Heterozigoto , Humanos , Desequilíbrio de Ligação/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
The BRIP1 gene encodes a helicase interacting with BRCA1, which contributes to BRCA1-associated DNA repair function. Germ-line BRIP1 mutations affecting the helicase domain activity have been identified in early onset breast cancer patients. In addition, BRIP1 was recently identified as deficient in Fanconi anemia (FA) complementation group J. Given the growing evidence now linking BRCA1, BRCA2, and the FA pathway, as well as the involvement of FA proteins (BRCA2/FANCD1 and PALB2/FANCN) in breast cancer susceptibility, we sought to evaluate the contribution of FANCJ gene alterations regarding breast cancer susceptibility among our cohort of 96 breast cancer individuals from high-risk non-BRCA1/2 French Canadian families. No deleterious mutation, exon deletion, or retention of intronic portions could be identified. However, extensive analysis of the promoter and whole exonic and flanking intronic regions of FANCJ led to the identification of 42 variants, including 22 novel variants not previously reported, four of which were located in the promoter region. Transcription factors analysis revealed a potential involvement of FANCJ promoter variants in regulation of FANCJ expression, and reporter gene assays were performed. The allelic frequency was assessed in a cohort of 73 unaffected French Canadian individuals, and haplotype analysis and tagging single nucleotide polymorphism (SNP) identification were also performed. Although our study unlikely involves FANCJ as a high-risk predisposition gene in non-BRCA1/2 high-risk French Canadian families, the possible association of FANCJ missense variants with phenotypes associated with FA, such as childhood cancer, cannot be excluded.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Neoplasias da Mama/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Predisposição Genética para Doença , RNA Helicases/genética , Adulto , Idoso , Substituição de Aminoácidos/genética , Proteínas Reguladoras de Apoptose , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudos de Casos e Controles , Linhagem Celular Transformada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Cowden syndrome is a disease associated with an increase in breast cancer susceptibility. Alleles in PTEN and other breast cancer susceptibility genes would be responsible for approximately 25% of the familial component of breast cancer risk, BRCA1 and BRCA2 being the two major genes responsible for this inherited risk. In order to evaluate the proportion of high-risk French Canadian non-BRCA1/BRCA2 breast/ovarian cancer families potentially harboring a PTEN germline mutation, the whole coding and flanking intronic sequences were analyzed in a series of 98 breast cancer cases. Although no germline mutation has been identified in the coding region, our study led to the identification of four intronic variants. Further investigations were performed to analyze the effect of these variants, alone and/or in combination, on splicing and PTEN protein levels. Despite suggestive evidence emerging from in silico analyses, the presence of these intronic variants do not seem to alter RNA splicing or PTEN protein levels. In addition, as loss of PTEN or part of it has been reported, Western blot analysis has also been performed. No major deletion could be identified in our cohort. Therefore, assuming a Poisson distribution for the frequency of deleterious mutation in our cohort, if the frequency of such deleterious mutation was 2%, we would have had a 90% or greater chance of observing at least one such mutation. These results suggest that PTEN germline mutations are rare and are unlikely to account for a significant proportion of familial breast cancer cases in the French Canadian population.