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1.
medRxiv ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33173903

RESUMO

Anti-Müllerian hormone (AMH) is expressed by antral stage ovarian follicles in women. Consequently, circulating AMH levels are detectable until menopause. Variation in age-specific AMH levels has been associated with breast cancer and polycystic ovary syndrome (PCOS), amongst other diseases. Identification of genetic variants underlying variation in AMH levels could provide clues about the physiological mechanisms that explain these AMH-disease associations. To date, only one variant in MCM8 has been identified to be associated with circulating AMH levels in women. We aimed to identify additional variants for AMH through a GWAS meta-analysis including data from 7049 premenopausal women of European ancestry, which more than doubles the sample size of the largest previous GWAS. We identified four loci associated with AMH levels at p < 5×10 -8 : the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 , and CDCA7 . The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among SNPs for AMH levels and for age at menopause (r g = 0.82, FDR=0.003). Exploratory Mendelian randomization analyses did not support a causal effect of AMH on breast cancer or PCOS risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. In conclusion, we identified a variant in the AMH gene and three other loci that may affect circulating AMH levels in women.

2.
Cancer Epidemiol Biomarkers Prev ; 29(4): 860-870, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32051193

RESUMO

BACKGROUND: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. METHODS: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. RESULTS: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. CONCLUSIONS: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. IMPACT: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

3.
Nat Commun ; 10(1): 3927, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.


Assuntos
Cromossomos Humanos Par 2/genética , Citocinas/genética , Feto/metabolismo , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/genética
4.
Am J Clin Nutr ; 103(1): 39-49, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26675774

RESUMO

BACKGROUND: An understanding of whether homocysteine is a cause or a marker of increased blood pressure is relevant because blood homocysteine can be effectively lowered by safe and inexpensive interventions (e.g., vitamin B-6, B-9, and B-12 supplementation). OBJECTIVE: The aim was to assess the causal influence of homocysteine on systolic and diastolic blood pressure (SBP and DBP, respectively) in adults with the use of Mendelian randomization (MR). DESIGN: Data from the 1982 Pelotas Birth Cohort (Brazil) were used. A total of 4297 subjects were evaluated in 2004-2005 (mean age: 22.8 y). The association of homocysteine concentration with SBP and DBP was assessed by conventional ordinary least-squares (OLS) linear regression and 2-stage least-squares (2SLS) regression (MR analysis). The single nucleotide polymorphism (SNP) methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) was used as proxy for homocysteine concentration. We also applied MR to data from the International Consortium for Blood Pressure (ICBP) genomewide association studies (>69,000 participants) using rs1801133 and additional homocysteine-associated SNPs as instruments. RESULTS: In OLS regression, a 1-SD unit increase in log homocysteine concentration was associated with an increase of 0.9 (95% CI: 0.4, 1.4) mm Hg in SBP and of 1.0 (95% CI: 0.6, 1.4) mm Hg in DBP. In 2SLS regression, for the same increase in homocysteine, the coefficients were -1.8 mm Hg for SBP (95% CI: -3.9, 0.4 mm Hg; P = 0.01) and 0.1 mm Hg for DBP (95% CI: -1.5, 1.7 mm Hg; P = 0.24). In the MR analysis of ICBP data, homocysteine concentration was not associated with SBP (ß = 0.6 mm Hg for each 1-SD unit increase in log homocysteine; 95% CI: -0.8, 1.9 mm Hg) but was positively associated with DBP (ß = 1.1 mm Hg; 95% CI: 0.2, 1.9 mm Hg). The association of genetically increased homocysteine with DBP was not consistent across different SNPs. CONCLUSION: Overall, the present findings do not corroborate the hypothesis that homocysteine has a causal role in blood pressure, especially in SBP.


Assuntos
Pressão Sanguínea , Homocisteína/sangue , Hipertensão/sangue , Adulto , Biomarcadores/sangue , Determinação da Pressão Arterial , Brasil , Estudos de Coortes , Feminino , Homocisteína/genética , Humanos , Hipertensão/etiologia , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
5.
Int J Vitam Nutr Res ; 83(5): 299-310, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-25305225

RESUMO

The aim of this study was to investigate the real impact of dietary lipids on metabolic and inflammatory response in rat white adipose tissue. Male healthy Wistar rats were fed ad libitum with a control diet (CON, n=12) or with an adjusted high-fat diet (HFD, n=12) for 12 weeks. Oral glucose and insulin tolerance tests were performed during the last week of the protocol. Plasma fatty acid, lipid profile, body adiposity, and carcass chemical composition were analyzed. Plasma concentration of leptin, adiponectin, C-reactive protein (CRP), TNF-α, IL-6, and monocyte chemotactic protein (MCP-1) was measured. Periepididymal adipose tissue was employed to evaluate TNF-α, MCP-1, and adiponectin gene expression as well as NF-κB pathway and AKT proteins. Isocaloric intake of the adjusted HFD did not induce hyperphagia, but promoted an increase in periepididymal (HFD = 2.94 ± 0.77 vs. CON = 1.99 ± 0.26 g/100 g body weight, p = 0.01) and retroperitoneal adiposity (HFD = 3.11 ± 0.81 vs. CON = 2.08 ± 0.39 g/100 g body weight, p = 0.01) and total body lipid content (HFD = 105.3 ± 20.8 vs. CON = 80.5 ± 7.6 g carcass, p = 0.03). Compared with control rats, HFD rats developed glucose intolerance (p=0.01), dyslipidemia (p = 0.02) and exhibited higher C-reactive protein levels in response to the HFD (HFD = 1002 ± 168 vs. CON = 611 ± 260 ng/mL, p = 0.01). The adjusted HFD did not affect adipokine gene expression or proteins involved in inflammatory signaling, but decreased AKT phosphorylation after insulin stimulation in periepididymal adipose tissue (p = 0.01). In this study, nutrient-adjusted HFD did not induce periepididymal adipose tissue inflammation in rats, suggesting that the composition of HFD differently modulates inflammation in rats, and adequate micronutrient levels may also influence inflammatory pathways.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica/métodos , Gorduras na Dieta/sangue , Epididimo/efeitos dos fármacos , Inflamação/sangue , Micronutrientes/sangue , Animais , Western Blotting/métodos , Dieta/métodos , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose/métodos , Teste de Tolerância a Glucose/estatística & dados numéricos , Insulina/sangue , Resistência à Insulina , Masculino , Reação em Cadeia da Polimerase/métodos , Ratos , Ratos Wistar
6.
Nutrition ; 29(2): 443-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23085013

RESUMO

OBJECTIVE: The present study was designed to investigate the effect of a high-fat diet (HFD) on the inflammatory response of peritoneal macrophages. METHODS: Male Wistar rats were fed a control diet (n = 12) or an HFD (n = 12) for 12 wk. After euthanasia, peritoneal macrophages were collected and stimulated (or not) with lipopolysaccharide (LPS). Results from the assays using peritoneal macrophages were analyzed with one-way analysis of variance or an equivalent non-parametric test. The level of significance adopted was 0.05. RESULTS: Consumption of the HFD was associated with significant increases in weight gain and fat depots (P < 0.05). Despite having no influence in systemic markers of inflammation, such as interleukin (IL)-6, tumor necrosis factor-α, and plasminogen activator inhibitor-1, the HFD intake significantly decreased insulin sensitivity, as evaluated by the homeostasis model assessment index (P < 0.05). A decreased production of IL-1ß, IL-6, IL-10, and nitric oxide in response to the LPS stimulation was observed in peritoneal macrophages from the HFD group (P < 0.05). Also, in HFD-fed animals, LPS incubation did not increase IL-1ß and IL-6 mRNA expression (P < 0.05). These effects were associated with an attenuation of IκB inhibitor kinase-ß phosphorylation and nuclear factor-κB activation in response to LPS and with a failure to decrease IκB inhibitor-α expression (P < 0.05). CONCLUSION: Chronic consumption of an HFD decreased the LPS-induced inflammatory response of peritoneal macrophages, which was associated with a downregulation of the nuclear factor-κB signaling pathway.


Assuntos
Dieta Hiperlipídica , Macrófagos Peritoneais/metabolismo , NF-kappa B/genética , Transdução de Sinais , Animais , Biomarcadores/sangue , Células Cultivadas , Regulação para Baixo , Inflamação/metabolismo , Resistência à Insulina , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Lipopolissacarídeos/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico/sangue , Fosforilação , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue , Ganho de Peso
7.
Nutrition ; 27(4): 399-404, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20971616

RESUMO

Accumulating data support that vitamin D possesses several biological and molecular actions apart from its role in calcium homeostasis. Immune cells express vitamin D receptor and are capable of metabolizing vitamin D. Within this context, experimental studies show that vitamin D modulates immune and inflammatory responses. Epidemiologic evidence linking poor vitamin D status to autoimmune diseases, type 2 diabetes, and cardiovascular disease suggests that insufficient vitamin D may be involved in the etiology of such disorders. Given the impact of immune and inflammatory abnormalities in the development of chronic diseases, including autoimmune disorders, it is possible that vitamin D might reduce chronic disease risk by modulating the immune system.


Assuntos
Doenças Autoimunes/etiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Fatores Imunológicos/fisiologia , Inflamação , Deficiência de Vitamina D/complicações , Vitamina D/imunologia , Animais , Humanos , Receptores de Calcitriol , Vitamina D/fisiologia
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