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1.
Nature ; 575(7784): 652-657, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31748747

RESUMO

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

2.
Hum Mol Genet ; 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31630189

RESUMO

Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular related disease. We performed a genome-wide association study of ACR using 437,027 individuals from the UK Biobank in the discovery phase, 54,527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P<5x10-8), of which 20 were not previously reported. Pathway analyses and the identification of 20 of the 62 variants (at r2>0.8) coinciding with signals for at least sixteen related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes - a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P≤4x10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.

3.
Eur J Vasc Endovasc Surg ; 57(5): 639-648, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005508

RESUMO

OBJECTIVE: To report the outcome of elective fenestrated and branch (FEVAR-BEVAR) endovascular aortic repair with supracoeliac (SC) sealing zones and the impact of staged repair without prophylactic cerebrospinal fluid (CSF) drainage on the incidence of spinal cord ischaemia (SCI). METHODS: Two hundred and seventy consecutive patients (217 men; mean [SD] age, 72.8 ± 6.3 years; median (IQR) diameter 65 mm [62-75 mm]) with juxtarenal (JRAAA) (n = 69) or thoraco-abdominal aortic aneurysms (TAAAs) (n = 201) underwent elective FEVAR (n = 192) or BEVAR (n = 78) with renovisceral stent grafting, proximal SC (Zones 1-5; <40 mm [n = 83]; ≥40 mm [n = 187]) and distal infrarenal aorto-iliac sealing zone (Zones 9-11) between December 2008 and September 2017. A spinal cord protection protocol (SCPP) including staging without prophylactic CSF drainage was introduced in September 2012. RESULTS: A total of 1026 renovisceral vessels (mean 3.8 ± 0.5 per patient) were targeted for preservation. One patient (0.4%) died in the institution within 30 days and 31 (11.4%) developed 36 major non-fatal complications including unplanned permanent dialysis (n = 1, 0.4%) and non-ambulatory SCI (n = 6, 2.2%). In patients with <40 mm SC coverage, none were staged or had prophylactic CSF drains and none developed SCI. In patients with ≥40 mm SC coverage, SCI occurred in 3.3% (pre-SCPP: 4/20 [20%; none staged, 13 prophylactic CSF drains] vs. post-SCPP: 2/167 [1.2%; 89 staged, no prophylactic CSF drains]; p = .001 [OR = 19.9]). Estimated survival (±SE) at one, two and three years was 92.6% ± 1.6%, 86.5% ± 2.4%, and 73.8% ± 3.5%, respectively, with no significant difference comparing extent of aneurysm or SC coverage. Forty-three (15.9%) patients required late re-intervention. Estimated freedom from re-intervention at one, two and three years was 91.9% ± 1.8%, 85.1% ± 2.5%, and 79.5% ± 3.2%, respectively. CONCLUSION: Elective endovascular thoraco-abdominal aortic repair with SC sealing zones can be performed with low peri-operative risk and good medium-term outcomes. Selective staging without prophylactic CSF drainage contributed to a significant reduction in the incidence of SCI.


Assuntos
Aneurisma da Aorta Torácica/cirurgia , Procedimentos Cirúrgicos Eletivos/métodos , Procedimentos Endovasculares/métodos , Idoso , Vazamento de Líquido Cefalorraquidiano , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Feminino , Seguimentos , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias , Reoperação , Estudos Retrospectivos , Isquemia do Cordão Espinal/etiologia , Isquemia do Cordão Espinal/prevenção & controle , Resultado do Tratamento
4.
Nat Commun ; 10(1): 1585, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952852

RESUMO

Sleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P < 5 × 10-8, of which 20 reach a stricter threshold of P < 8 × 10-10. These include 26 novel associations with measures of sleep quality and 10 with nocturnal sleep duration. The majority of identified variants associate with a single sleep trait, except for variants previously associated with restless legs syndrome. For sleep duration we identify a missense variant (p.Tyr727Cys) in PDE11A as the likely causal variant. As a group, sleep quality loci are enriched for serotonin processing genes. Although accelerometer-derived measures of sleep are imperfect and may be affected by restless legs syndrome, these findings provide new biological insights into sleep compared to previous efforts based on self-report sleep measures.


Assuntos
Polissonografia/métodos , Transtornos do Sono-Vigília/genética , Sono/genética , Acelerometria/métodos , Ritmo Circadiano , Humanos , Polimorfismo de Nucleotídeo Único , Serotonina/genética , Serotonina/metabolismo , Transtornos do Sono-Vigília/diagnóstico , Relação Cintura-Quadril
5.
Hum Mol Genet ; 28(8): 1392-1401, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30649302

RESUMO

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.


Assuntos
Hormônio Antimülleriano/genética , Pré-Menopausa/fisiologia , Adulto , Fatores Etários , Hormônio Antimülleriano/sangue , Hormônio Antimülleriano/fisiologia , Sequência de Bases , Feminino , Expressão Gênica , Regulação da Expressão Gênica/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Longevidade , Menarca/genética , Pessoa de Meia-Idade , Mitocôndrias/genética , Folículo Ovariano , Ovário , Polimorfismo de Nucleotídeo Único/genética , Pré-Menopausa/genética , Reprodução/genética , Análise de Sequência de DNA , Transcriptoma/genética
6.
Nat Commun ; 10(1): 343, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696823

RESUMO

Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.


Assuntos
Ritmo Circadiano , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , AMP Cíclico/metabolismo , Feminino , Loci Gênicos , Ácido Glutâmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Sono , Reino Unido
7.
J Am Chem Soc ; 141(1): 298-308, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525570

RESUMO

Molecular inks based on dimethyl sulfoxide, thiourea (TU), and metal salts have been used to form high optoelectronic quality semiconductors and have led to high power conversion efficiencies for solution-processed photovoltaic devices for Cu2ZnSn(S,Se)4 (CZTS), Cu2Zn(Ge,Sn)(S,Se)4 (CZGTS), CuIn(S,Se)2 (CIS), and Cu(In,Ga)(S,Se)2 (CIGS). However, several metal species of interest, including Ag(I), In(III), Ge(II), and Ge(IV), either have low solubility (requiring dilute inks) or lead to precipitation or gelation. Here, we demonstrate that the combination of N,N-dimethylformamide (DMF) and TU has the remarkable ability to form intermediate-stability acid-base complexes with a wide number of metal chloride Lewis acids (CuCl, AgCl, ZnCl2, InCl3, GaCl3, SnCl4, GeCl4, and SeCl4), to give high-concentration stable molecular inks. Using calorimetry, Raman spectroscopy, and solubility experiments, we reveal the important role of chloride transfer and TU to stabilize metal cations in DMF. Methylation of TU is used to vary the strength of the Lewis basicity and demonstrate that the strength of the TU-metal chloride complex formed after DMF evaporation is critical to prevent volatilization of metal containing species. Further, we formulated a sulfur-free molecular ink which was used to deposit crystalline CuInSe2 without selenization that sustains high quasi-Fermi level splitting under constant illumination. Finally, we demonstrate the ability of the DMF-TU molecular ink chemistry to lead to high-photovoltaic power conversion efficiencies and high-open-circuit voltages for solution-processed CIS and CZGTS with power conversion efficiencies of 13.4% and 11.0% and Voc/ Voc,SQ of 67% and 63%, respectively.

9.
Am J Hum Genet ; 104(1): 157-163, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583798

RESUMO

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Disfunção Erétil/etiologia , Disfunção Erétil/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipotálamo/patologia , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromossomos Humanos Par 6/genética , Simulação por Computador , Europa (Continente) , Humanos , Masculino , Proteínas Repressoras/genética
10.
Int J Epidemiol ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30423117

RESUMO

Background: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. Methods: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Results: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Conclusions: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

11.
Diabetes ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352878

RESUMO

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such "favourable adiposity" alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging (MRI) data with genome-wide association studies (GWAS) of body fat % and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity, but a favourable metabolic profile. Consistent with previous studies, individuals carrying more "favourable adiposity" alleles had higher body fat % and higher BMI, but lower risk of type 2 diabetes, heart disease and hypertension. These individuals also had higher subcutaneous fat, but lower liver fat and lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14 and IRS1, whilst the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified "favourable adiposity" alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in metabolically low risk depots.

12.
J Appl Anim Welf Sci ; : 1-13, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30295508

RESUMO

As nonhuman animals age, geriatric individuals require additional care and veterinary support to ensure their well being. The focus on lifelong care is a relatively newer approach when providing good welfare, and few studies have examined how veterinary care impacts behavior at different ages or how best to accommodate geriatric individuals in zoos. The objectives of this study were to (a) assess both the immediate and long-term (one year later) behavioral impacts of cataract removal for macaroni (Eudyptes chrysolophus) and southern rockhopper (Eudyptes chrysocome) penguins; (b) compare the behavior of penguins following cataract surgery to that of other conspecifics in the same habitat; and (c) monitor the impacts of cataract surgery on swimming behavior using time-depth recorders. Individual responses to cataract removal differed in direction and magnitude, and these mixed results highlight that welfare is experienced and thus measured at the individual level. Positive responses included increased habitat use, increased time spent swimming, and increased rates of affiliative interactions. This study highlights the importance of assessing welfare impacts of veterinary interventions on geriatric individuals.

13.
Genet Med ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30181606

RESUMO

PURPOSE: Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the penetrance has been overestimated. METHODS: We characterized the prevalence and phenotypic consequences of X chromosome aneuploidy in a population of 244,848 women over 40 years of age from UK Biobank, using single-nucleotide polymorphism (SNP) array data. RESULTS: We detected 30 women with 45,X; 186 with mosaic 45,X/46,XX; and 110 with 47,XXX. The prevalence of nonmosaic 45,X (12/100,000) and 47,XXX (45/100,000) was lower than expected, but was higher for mosaic 45,X/46,XX (76/100,000). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognized Turner syndrome phenotype, including short stature and primary amenorrhea. In contrast, women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. The phenotype of women with 47,XXX included taller stature (5.3 cm; SD = 5.52 cm; P = 5.8 × 10-20) and earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 × 10-14). CONCLUSION: Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.

15.
PeerJ ; 6: e4824, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29844976

RESUMO

Invasive species management can be a victim of its own success when decades of effective control cause memories of past harm to fade and raise questions of whether programs should continue. Economic analysis can be used to assess the efficiency of investing in invasive species control by comparing ecosystem service benefits to program costs, but only if appropriate data exist. We used a case study of water hyacinth (Eichhornia crassipes (Mart.) Solms), a nuisance floating aquatic plant, in Louisiana to demonstrate how comprehensive record-keeping supports economic analysis. Using long-term data sets, we developed empirical and spatio-temporal simulation models of intermediate complexity to project invasive species growth for control and no-control scenarios. For Louisiana, we estimated that peak plant cover would be 76% higher without the substantial growth rate suppression (84% reduction) that appeared due primarily to biological control agents. Our economic analysis revealed that combined biological and herbicide control programs, monitored over an unusually long time period (1975-2013), generated a benefit-cost ratio of about 34:1 derived from the relatively modest costs of $124 million ($2013) compared to the $4.2 billion ($2013) in benefits to anglers, waterfowl hunters, boating-dependent businesses, and water treatment facilities over the 38-year analysis period. This work adds to the literature by: (1) providing evidence of the effectiveness of water hyacinth biological control; (2) demonstrating use of parsimonious spatio-temporal models to estimate benefits of invasive species control; and (3) incorporating activity substitution into economic benefit transfer to avoid overstating benefits. Our study suggests that robust and cost-effective economic analysis is enabled by good record keeping and generalizable models that can demonstrate management effectiveness and promote social efficiency of invasive species control.

16.
Cell Rep ; 23(2): 327-336, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29641994

RESUMO

Fibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21's mechanisms and therapeutic potential.

17.
J Water Health ; 16(1): 70-77, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29424720

RESUMO

In microbiological water quality testing, sample dechlorination with sodium thiosulfate is recommended to ensure that results accurately reflect the water quality at sample collection. Nevertheless, monitoring institutions in low-resource settings do not always dechlorinate samples, and there is limited research describing how this practice impacts drinking water quality results. The effect of dechlorination on indicator bacteria counts was evaluated by spiking laboratory water with five Escherichia coli (E. coli) concentrations (104-108 CFU/100 mL), chlorinating at six doses (0-0.6 mg/L), holding samples with and without sodium thiosulfate for 5-7 hours, and enumerating E. coli by membrane filtration with m-lauryl sulfate media. Additionally, sub-Saharan African water suppliers enumerated thermotolerant coliform by membrane filtration in paired chlorinated water samples collected with and without sodium thiosulfate. Across all E. coli and chlorine doses in the laboratory, and all field tests, samples held without sodium thiosulfate had lower bacteria counts (p < 0.001). Additionally, chlorinated water supply samples held without sodium thiosulfate had an 87.5% false negative rate. Results indicate the importance of dechlorinating microbiological water quality samples, discarding data from chlorinated samples collected without dechlorination, and reinforcing dechlorination recommendations in resource-limited environments to improve water safety management.


Assuntos
Cloro/química , Água Potável/química , Escherichia coli/isolamento & purificação , Fezes/microbiologia , Tiossulfatos/química , Microbiologia da Água , Purificação da Água/métodos , Qualidade da Água , África ao Sul do Saara , Halogenação
18.
Hum Mol Genet ; 27(4): 742-756, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309628

RESUMO

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

19.
J Clin Endocrinol Metab ; 103(3): 991-1004, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325096

RESUMO

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective: To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures: Genetic determinants of serum E2 and E1 levels. Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.


Assuntos
Aromatase/genética , Densidade Óssea/genética , Estradiol/sangue , Densidade Óssea/fisiologia , Cromossomos Humanos X , Estudos de Coortes , Estradiol/genética , Estradiol/fisiologia , Estrona/sangue , Estrona/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Genótipo , Hormônios Esteroides Gonadais/sangue , Humanos , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Vértebras Lombares/fisiologia , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Testosterona/sangue
20.
Zoo Biol ; 37(1): 23-34, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29210099

RESUMO

We investigated how forage material affects indicators of welfare in three male Western lowland gorillas (Gorilla gorilla gorilla) at the Detroit Zoo. In addition to their maintenance diet and enrichment foods, the gorillas generally received forage material four times a week. From this baseline, we systematically manipulated how much forage material the group received on a weekly basis, with either daily or bi (twice)-weekly presentation of browse (mulberry, Morus sp.) or alfalfa hay. We collected behavioral data (60 hr per gorilla) and measured fecal glucocorticoid metabolites (FGM). Mixed models indicated that the presence of forage material significantly increased time feeding (F2,351 = 9.58, p < 0.001), and decreased rates of noncontact aggression (F2,351 = 3.69, p = 0.03), and regurgitation and reingestion (F2,353 = 4.70, p = 0.01). Regurgitation and reingestion were never observed during the condition when forage material was provided daily. When forage material was provided, time spent feeding was similar across gorillas, compared to a disproportionately greater amount of time spent feeding by the dominant individual when forage material was absent. Providing forage material in addition to the regular diet likely created more opportunities for equitable feeding for the subordinate gorillas. FGM concentrations did not vary based on the presence or type of forage material available and, instead, likely reflected group social dynamics. In general, alfalfa and mulberry had similar impacts on behavior, indicating that alfalfa can be an adequate behavioral substitute during times when browse is less readily available for gorillas housed in seasonally variable climates.


Assuntos
Ração Animal/análise , Comportamento Animal , Glucocorticoides/metabolismo , Gorilla gorilla , Medicago sativa , Morus , Criação de Animais Domésticos , Animais , Animais de Zoológico , Fezes/química , Glucocorticoides/química , Masculino , Atividade Motora
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