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1.
Mol Nutr Food Res ; : e1900226, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31432628

RESUMO

SCOPE: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1ß inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors. METHODS: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance. RESULTS: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (ß ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. CONCLUSION: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.

2.
Nat Genet ; 51(8): 1207-1214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31308545

RESUMO

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

3.
J Med Food ; 22(7): 729-740, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31290733

RESUMO

Diet is a modifiable key factor targeted in prevention and management of nonalcoholic fatty liver disease (NAFLD). The aim was to study the effect of Mediterranean Diet (MedDiet) on clinical, biochemical, and inflammatory profile in NAFLD patients with simple steatosis. Potential associations of signal transducer and activator of transcription 3 (STAT3) rs2293152 genotype to diet composition and patients' profile were investigated. In this nonrandomized, open-label, 24-week prospective intervention study, 44 untreated NAFLD patients with nonsignificant fibrosis received nutritional counsel to increase adherence to MedDiet. Adherence to MedDiet was estimated with MedDietScore. Furthermore, we genotyped STAT3 rs2293152 single nucleotide polymorphism and performed clinical and inflammatory measurements. In all patients, MedDietScore increased and anthropometric indices improved, whereas liver imaging, liver fibrosis score, blood pressure, fasting glucose, glycated hemoglobin (HbA1c), C-reactive protein (CRP), visfatin, and oxidized low-density lipoprotein levels were also significantly ameliorated compared with baseline (P < .05). No association of STAT3 polymorphism with diet composition was found. Comparisons of mean differences between G- and C-carriers at the end point of the trial showed that only visfatin was significantly associated with the STAT3 genotype (-0.0 ± 4.6 vs. -4.2 ± 3.9, P = .04, respectively). Carrying the G-allele was associated with an increase of the visfatin levels (3.4 ± 1.5 ng/mL, P = .028). Our results show amelioration of clinical, biochemical, and inflammatory biomarkers in NAFLD patients in response to MedDiet. STAT3 rs2293152 G-carriers experienced more beneficial changes at the end of the intervention compared with baseline. An association between visfatin levels and STAT3 genotype has been shown for the first time.

4.
J Bone Miner Res ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170332

RESUMO

In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (ß = 0.20, p = 4.6 × 10-49 ) and GALNT1 (ß = 0.11 per G allele, p = 4.4 × 10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (ß = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (ß = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (ß = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

5.
Pharmacogenomics ; 20(9): 643-657, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31250730

RESUMO

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005.

6.
Nutrition ; 61: 105-110, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30708259

RESUMO

OBJECTIVE: The aim of this study was to test the hypothesis that posteriori-derived dietary patterns of a Greek sample are associated with the odds for non-alcoholic fatty liver disease (NAFLD) and common NAFLD-related biomarkers. METHODS: We recruited 351 individuals (134 NAFLD patients, 217 controls). NAFLD was diagnosed with abdominal ultrasound. Dietary intake data were collected through a semi-quantitative food frequency questionnaire of 172 items and dietary patterns were derived by factor analysis. Consumption of dietary patterns was divided into quartiles. Multivariate logistic and linear regression models were applied to investigate associations of dietary patterns with NAFLD odds and common NAFLD-associated biomarkers. RESULTS: Four dietary patterns were identified. Adherence to the fast food-type dietary pattern was independently associated with higher odds for NAFLD. However, results were statistically significant only for the highest versus the lowest consumption (odds ratio, 3.9; P = 0.003). On the contrary, individuals in the second quartile of the unsaturated fatty acid dietary pattern had 55.7% reduced odds of developing NAFLD than those in the first quartile after adjusting for age, sex, energy intake, physical activity level, pack-years smoked, education years, and presence of metabolic syndrome (P = 0.039). The fast food-type pattern was further associated with higher levels of C-reactive protein and uric acid and the unsaturated fatty acid pattern with reduced levels of insulin and homeostatic model assessment of insulin resistance (P < 0.05). The prudent dietary pattern was associated with decreased triacylglycerol and uric acid levels (ß = -5.960; P = 0.037 and ß = -0.153; P = 0.035, respectively). CONCLUSION: This is the first study to indicate associations of dietary patterns with NAFLD in a European population.

7.
Nat Commun ; 10(1): 357, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664637

RESUMO

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.


Assuntos
Alelos , Loci Gênicos , Variação Genética , RNA Mensageiro/genética , Crânio/metabolismo , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Crânio/anatomia & histologia
8.
Bioinformatics ; 35(15): 2555-2561, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576415

RESUMO

MOTIVATION: Very low-depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterization of the genotype quality and association power for very low-depth sequencing designs is still lacking. RESULTS: We perform cohort-wide whole-genome sequencing (WGS) at low depth in 1239 individuals (990 at 1× depth and 249 at 4× depth) from an isolated population, and establish a robust pipeline for calling and imputing very low-depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (75× depth) and high-depth (22×) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1× WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1× further allowed the discovery of 140 844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low-depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design. AVAILABILITY AND IMPLEMENTATION: The HELIC genotype and WGS datasets have been deposited to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home): EGAD00010000518; EGAD00010000522; EGAD00010000610; EGAD00001001636, EGAD00001001637. The peakplotter software is available at https://github.com/wtsi-team144/peakplotter, the transformPhenotype app can be downloaded at https://github.com/wtsi-team144/transformPhenotype. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

9.
Nat Commun ; 9(1): 5460, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568165

RESUMO

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items "rare" and "common" were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.

10.
Transl Psychiatry ; 8(1): 252, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30470734

RESUMO

The epidemiologic link between schizophrenia (SCZ) and type 2 diabetes (T2D) remains poorly understood. Here, we investigate the presence and extent of a shared genetic background between SCZ and T2D using genome-wide approaches. We performed a genome-wide association study (GWAS) and polygenic risk score analysis in a Greek sample collection (GOMAP) comprising three patient groups: SCZ only (n = 924), T2D only (n = 822), comorbid SCZ and T2D (n = 505); samples from two separate Greek cohorts were used as population-based controls (n = 1,125). We used genome-wide summary statistics from two large-scale GWAS of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform genetic overlap analyses, including a regional colocalisation test. We show for the first time that patients with comorbid SCZ and T2D have a higher genetic predisposition to both disorders compared to controls. We identify five genomic regions with evidence of colocalising SCZ and T2D signals, three of which contain known loci for both diseases. We also observe a significant excess of shared association signals between SCZ and T2D at nine out of ten investigated p value thresholds. Finally, we identify 29 genes associated with both T2D and SCZ, several of which have been implicated in biological processes relevant to these disorders. Together our results demonstrate that the observed comorbidity between SCZ and T2D is at least in part due to shared genetic mechanisms.

11.
Nat Commun ; 9(1): 4674, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405126

RESUMO

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10-8; APOC3 and triglyceride levels, P = 1.5 × 10-26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10-8), indicating a role for this gene in lipid metabolism.

13.
Arch Osteoporos ; 13(1): 111, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30324335

RESUMO

Vitamin D deficiency and quantitative ultrasound measurements are associated with bone fragility. We assessed these parameters and their correlates. 87.7% of the population has vitamin D inadequacy and this correlated with lifestyle factors. These results contribute to epidemiological data needed for population guidelines for bone health. PURPOSE: Vitamin D deficiency and quantitative ultrasound (QUS) parameters are among the most important clinical risk factors of bone fragility. Few data are available for Greek population. The aim of the study was to evaluate the serum 25-hydroxyvitamin D [25(OH)D] level and their determinants, as well as QUS parameters in Greek population. METHODS: OSTEOS is an observational cross-sectional study conducted from June 2010 to July 2012. Nine hundred seventy adults were recruited from rural and urban areas throughout Greece and completed the appropriate questionnaire. Serum 25(OH)D measured by enzyme immunoassay, QUS parameters, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI), was assessed with an Achilles device. Univariate Analysis of Variance was used for the assessment of serum 25(OH)D determinants. RESULTS: Mean serum 25(OH)D of the total population was 20,00 ± 8,00 ng/mL. Females had lower levels than males. The negative determinants of serum 25(OH)D in the total population were the female sex and the winter-spring season of sampling while age proved negative association solely in obese subjects. Positive determinants of vitamin D status were summer sun exposure and organized physical activity as expected. Urban had lower SOS and SI than rural residents. Individuals with 25(OH)D ≥ 20 ng/mL had higher SOS than those with 25(OH)D < 20 ng/mL. BUA, SOS, and SI are positively correlated with organized physical activity and negatively with PTH. CONCLUSIONS: This study reports that vitamin D deficiency is highly prevalent among healthy Greek men and women, demonstrates the multifactorial causation of 25(OH)D levels, and points out that further research is required to determine more factors related to vitamin D status and bone health.

14.
BMC Psychiatry ; 18(1): 249, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30071838

RESUMO

BACKGROUND: Schizophrenia (SCZ) is associated with increased risk of type 2 diabetes (T2D). The potential diabetogenic effect of concomitant application of psychotropic treatment classes in patients with SCZ has not yet been evaluated. The overarching goal of the Genetic Overlap between Metabolic and Psychiatric disease (GOMAP) study is to assess the effect of pharmacological, anthropometric, lifestyle and clinical measurements, helping elucidate the mechanisms underlying the aetiology of T2D. METHODS: The GOMAP case-control study (Genetic Overlap between Metabolic and Psychiatric disease) includes hospitalized patients with SCZ, some of whom have T2D. We enrolled 1653 patients with SCZ; 611 with T2D and 1042 patients without T2D. This is the first study of SCZ and T2D comorbidity at this scale in the Greek population. We retrieved detailed information on first- and second-generation antipsychotics (FGA, SGA), antidepressants and mood stabilizers, applied as monotherapy, 2-drug combination, or as 3- or more drug combination. We assessed the effects of psychotropic medication, body mass index, duration of schizophrenia, number of hospitalizations and physical activity on risk of T2D. Using logistic regression, we calculated crude and adjusted odds ratios (OR) to identify associations between demographic factors and the psychiatric medications. RESULTS: Patients with SCZ on a combination of at least three different classes of psychiatric drugs had a higher risk of T2D [OR 1.81 (95% CI 1.22-2.69); p = 0.003] compared to FGA alone therapy, after adjustment for age, BMI, sex, duration of SCZ and number of hospitalizations. We did not find evidence for an association of SGA use or the combination of drugs belonging to two different classes of psychiatric medications with increased risk of T2D [1.27 (0.84-1.93), p = 0.259 and 0.98 (0.71-1.35), p = 0.885, respectively] compared to FGA use. CONCLUSIONS: We find an increased risk of T2D in patients with SCZ who take a combination of at least three different psychotropic medication classes compared to patients whose medication consists only of one or two classes of drugs.

15.
Biol Trace Elem Res ; 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30014284

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. Its global prevalence is estimated between 25 and 45%, occurring mainly in overweight individuals with unhealthy dietary habits and low levels of physical activity. Many studies have investigated the association of trace elements with liver diseases, though not with NAFLD. In this work, we investigated trace element levels in plasma of patients and not-patients and their possible association with various stages of the disease. Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the determination of As, Ba, Cd, Co, Cs, Cu, Fe, Rb, Sr, Tl, and Zn in the plasma of 189 free-living residents of Athens, Greece, either healthy or patients with mild, moderate, or severe NAFLD. The disease was diagnosed by abdominal ultrasound; blood samples were analyzed for total, HDL and LDL cholesterol, triglycerides, fasting glucose, fasting insulin, and liver enzymes, namely aspartate aminotransferase (AST), alanine transaminase (ALT), and γ-glutamyltransferase (Gamma-GT); insulin resistance was determined by the homeostatic model assessment (HOMA-IR). Zinc exhibited a statistically significant negative association with the severity of the disease, while cesium showed a statistically significant positive association. Moreover, thallium and iron were inversely associated with insulin levels. Trace element determination in plasma could be useful for establishing relationships with NAFLD status of patients. Further research is required for the verification and interpretation of these findings.

16.
Mol Psychiatry ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988085

RESUMO

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

18.
Nat Genet ; 50(2): 172-174, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29311636

RESUMO

We have identified a variant in ADCY3 (encoding adenylate cyclase 3) associated with markedly increased risk of obesity and type 2 diabetes in the Greenlandic population. The variant disrupts a splice acceptor site, and carriers have decreased ADCY3 RNA expression. Additionally, we observe an enrichment of rare ADCY3 loss-of-function variants among individuals with type 2 diabetes in trans-ancestry cohorts. These findings provide new information on disease etiology relevant for future treatment strategies.

20.
Eur J Nutr ; 57(6): 2227-2235, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28695325

RESUMO

AIM: To investigate the association between GCKR gene and nutritional treatment in NAFLD-related biomarkers. METHODS: This was an open-label and single-arm clinical trial in 44 overweight or obese adults with NAFLD receiving nutritional counseling for 6 months. Nutritional data, MedDietScore, clinical, biochemical, inflammatory and oxidative stress biomarkers were evaluated before and after intervention. Further, we genotyped GCKR rs1260326 and in T-allele carriers and non-Τ-carriers we assessed associations between the GCKR variant and nutritional counseling related to change in all biomarkers evaluated. RESULTS: Anthropometric measurements were significantly reduced after the end of the intervention in patients assigned to nutritional counseling. Liver imaging and fibrosis were significantly improved. GCKR rs1260326 T-allele frequency was 46.7%. T-carriers responded better to nutritional counseling regarding fasting blood glucose levels (mean6-0 change = -4.94 mg/dL (±9.33), p = 0.005), whereas non-T-carriers did not benefit from the intervention regarding glucose. On the other hand, levels of oxLDL decreased in the non-T-carriers group after the intervention, but not in T-carriers. CONCLUSIONS: Our results show that GCKR rs1260326 T-allele is associated with better response of NAFLD patients to nutritional treatment regarding fasting blood glucose, but not oxLDL levels. Despite this important finding in the field of nutrigenetics, it is tricky to generalize this effect unless larger studies are conducted.

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