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Mol Vis ; 25: 438-445, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523121


Purpose: To study the relationship between primary open-angle glaucoma (POAG) in a cohort of patients of African descent (AD) and serum vitamin D levels. Methods: A subset of the AD and glaucoma evaluation study III (ADAGES III) cohort, consisting of 357 patients with a diagnosis of POAG and 178 normal controls of self-reported AD, were included in this analysis. Demographic information, family history, and blood samples were collected from all the participants. All the subjects underwent clinical evaluation, including visual field (VF) mean deviation (MD), central cornea thickness (CCT), intraocular pressure (IOP), and height and weight measurements. POAG patients were classified into early and advanced phenotypes based on the severity of their visual field damage, and they were matched for age, gender, and history of hypertension and diabetes. Serum 25-Hydroxy (25-OH) vitamin D levels were measured by enzyme-linked immunosorbent assay (ELISA). The association of serum vitamin D levels with the development and severity of POAG was tested by analysis of variance (ANOVA) and the paired t-test. Results: The 178 early POAG subjects had a visual field MD of better than -4.0 dB, and the 179 advanced glaucoma subjects had a visual field MD of worse than -10 dB. The mean (95% confidence interval [CI]) levels of vitamin D of the subjects in the control (8.02 ± 6.19 pg/ml) and early phenotype (7.56 ± 5.74 pg/ml) groups were significantly or marginally significantly different from the levels observed in subjects with the advanced phenotype (6.35 ± 4.76 pg/ml; p = 0.0117 and 0.0543, respectively). In contrast, the mean serum vitamin D level in controls was not significantly different from that of the subjects with the early glaucoma phenotype (p = 0.8508). Conclusions: In this AD cohort, patients with advanced glaucoma had lower serum levels of vitamin D compared with early glaucoma and normal subjects.

Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226


Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
Hum Reprod ; 34(2): 335-344, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576500


STUDY QUESTION: Are non-esterified fatty acid (NEFA) kinetics altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS, particularly obese subjects, have dysregulated plasma NEFA kinetics in response to changes in plasma insulin and glucose levels, which are associated with insulin resistance (IR) independently of the fasting plasma NEFA levels. WHAT IS KNOWN ALREADY: Elevated plasma NEFA levels are associated with IR in many disorders, although the homeostasis of NEFA kinetics and its relationship to IR in women with PCOS is unknown. STUDY DESIGN, SIZE, DURATION: We prospectively compared insulin sensitivity and NEFA kinetics in 29 PCOS and 29 healthy controls women matched for BMI. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a tertiary institution. Plasma NEFA, glucose and insulin levels were assessed during a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT). Minimal models were used to assess insulin sensitivity (Si) and NEFA kinetics (i.e. model-derived initial plasma NEFA level [NEFA0], phi constant [Φ], reflecting glucose-mediated inhibition of lipolysis and measures of maximum rate of lipolysis [SFFA] and NEFA uptake from plasma [KFFA]). MAIN RESULTS AND THE ROLE OF CHANCE: The study provides new evidence that women with PCOS have defective NEFA kinetics characterized by: (i) lower basal plasma NEFA levels, measured directly and modeled (NEFA0), and (ii) a greater glucose-mediated inhibition of lipolysis in the remote or interstitial space (reflected by a lower affinity constant [Φ]). There were no differences, however, in the maximal rates of adipose tissue lipolysis (SFFA) and the rate at which NEFA leaves the plasma pool (KFFA). The differences observed in NEFA kinetics were exacerbated, and almost exclusively observed, in the obese PCOS subjects. LIMITATIONS, REASONS FOR CAUTION: Our study did not study NEFA subtypes. It was also cross-sectional and based on women affected by PCOS as defined by the 1990 National Institutes of Health (NIH) criteria (i.e. Phenotypes A and B) and identified in the clinical setting. Consequently, extrapolation of the present data to other phenotypes of PCOS should be made with caution. Furthermore, our data is exploratory and therefore requires validation with a larger sample size. WIDER IMPLICATIONS OF THE FINDINGS: Dysfunction in NEFA kinetics may be a marker of metabolic dysfunction in nondiabetic obese women with PCOS and may be more important than simply assessing circulating NEFA levels at a single point in time for understanding the mechanism(s) underlying the IR of PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by NIH grants R01-DK073632 and R01-HD29364 to R.A.; a Career Development Award from MD Medical Group, Moscow, RF, to D.L. and Augusta University funds to Y.-H.C. RA serves as consultant to Ansh Labs, Medtronics, Spruce Biosciences and Latitude Capital. U.E., Z.A., D.L., R.M., Y.-H.C., R.C.B. and Y.D.I.C. have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.