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1.
Hypertension ; 74(2): 375-383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230546

RESUMO

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.

2.
J Youth Adolesc ; 48(7): 1245-1263, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004264

RESUMO

School-based social and emotional learning programs aim to provide students with the skills they need to deal with life challenges, thereby enhancing their social and emotional wellbeing, academic outcomes, and reducing their risk of mental health difficulties. While there is a robust evidence base on the effectiveness of these programs originating from the US, there is a relative paucity of research on how these programs impact young people in other county contexts, especially for older adolescents and those at higher risk. This study sets out to address this research gap by evaluating the effectiveness of a social emotional learning program designed for older adolescents in Ireland, the MindOut program. MindOut is a universal school-based social and emotional learning program designed for older adolescents in Ireland which was developed based on a common elements approach underpinned by CASEL's framework. Employing a cluster randomized-controlled trial, data on social and emotional skills, academic performance and mental health outcomes were collected from students (n = 497; 51.1% female) ages 15-18 years in 32 disadvantaged schools. There were significant improvements in intervention students' social and emotional skills including, reduced suppression of emotions (p = 0.035), use of more positive coping strategies [reduced avoidance coping p = < 0.001) and increased social support coping p = 0.044)]. Improvements in mental health and wellbeing were also found with significantly reduced levels of stress (p = 0.017) and depressive symptoms (p = 0.030) as well as reduced anxiety scores for females students (p = 0.044). These short-term evaluation findings support the positive impact of school-based social and emotional learning programs, such as MindOut, when designed to be both age and culturally appropriate and delivered to older adolescents in disadvantaged schools.

3.
Biol Psychiatry ; 85(10): 838-849, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30905381

RESUMO

BACKGROUND: Exposure to early-life adversity is known to predict DNA methylation (DNAm) patterns that may be related to psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure. METHODS: Using a two-stage structured life course modeling approach, we tested the hypothesis that there are sensitive periods when adversity induces greater DNAm changes. We tested this hypothesis in relation to two alternatives: an accumulation hypothesis, in which the effect of adversity increases with the number of occasions exposed, regardless of timing; and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomic Studies, a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (n = 691-774). RESULTS: After covariate adjustment and multiple testing correction, we identified 38 CpG sites that were differentially methylated at 7 years of age following exposure to adversity. Most loci (n = 35) were predicted by the timing of adversity, namely exposures before 3 years of age. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard epigenome-wide association study of lifetime exposure (vs. no exposure) failed to detect these associations. CONCLUSIONS: The developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Very early childhood appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed versus unexposed to early-life adversity may dilute observed effects.

4.
Atherosclerosis ; 278: 190-196, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30296724

RESUMO

BACKGROUND AND AIMS: Sex differences in measures of cardiovascular health in adults are well documented. However, the sex-specific aetiology of cardiovascular health across childhood and adolescence is poorly understood. METHODS: We examined sex differences in trajectories of 11 measures of cardiovascular health from birth to 18 years, in a contemporary birth cohort study in England (N participants per outcomes: 662-13,985, N repeated measures per outcome: 1,831-112,768). Outcomes were measured over varying time spans from birth or mid-childhood to age 18 and with different numbers of repeated measures per outcome. Analyses were performed using fractional polynomial and linear spline multilevel models. RESULTS: Females had higher mean BMI, height-adjusted fat mass, pulse rate, insulin, triglycerides, and non-high-density lipoprotein cholesterol (HDL-c) and lower mean height-adjusted lean mass from birth or from mid-childhood to age 18. For example, mean non-HDL-c was 0.07 mmol/l (95% confidence interval (CI), 0.04, 0.10) higher in females compared with males at birth. By age 18, this difference persisted and widened to 0.19 mmol/l (95% CI, 0.16, 0.23) higher non-HDL-c in females compared with males. Females had lower levels of glucose from mid-childhood and developed lower systolic blood pressure and higher HDL-c from mid-adolescence onward. For example, females had 0.08 mmol/l (95% CI, 0.05, 0.10) lower mean glucose compared with males at age seven which widened to a difference of 0.22 mmol/l (95% CI, 0.25, 0.19) at age 18. CONCLUSIONS: Sex differences in measures of cardiovascular health are apparent from birth or mid-childhood and change during early life. These differences may have implications for sex-specific disease risk in future adult populations.

5.
Clin Epigenetics ; 10: 86, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983833

RESUMO

Background: Gestational age at delivery is associated with health and social outcomes. Recently, cord blood DNA methylation data has been used to predict gestational age. The discrepancy between gestational age predicted from DNA methylation and determined by ultrasound or last menstrual period is known as gestational age acceleration. This study investigated associations of sex, socioeconomic status, parental behaviours and characteristics and birth outcomes with gestational age acceleration. Results: Using data from the Avon Longitudinal Study of Parents and Children (n = 863), we found that pre-pregnancy maternal overweight and obesity were associated with greater gestational age acceleration (mean difference = 1.6 days, 95% CI 0.7 to 2.6, and 2.9 days, 95% CI 1.3 to 4.4, respectively, compared with a body mass index < 25 kg/m2, p < .001). There was evidence of an association between male sex and greater gestational age acceleration. Greater gestational age acceleration was associated with higher birthweight, birth length and head circumference of the child (mean differences per week higher gestational age acceleration: birthweight 0.1 kg, 95% CI 0.1 to 0.2, p < .001; birth length 0.4 cm, 95% CI 0.2 to 0.7, p < .001; head circumference 0.2 cm, 95% CI 0.1 to - 0.4, p < .001). There was evidence of an association between gestational age acceleration and mode of delivery (assisted versus unassisted delivery, odds ratio = 0.9 per week higher gestational age acceleration, 95% CI 0.7, 1.3 (p = .05); caesarean section versus unassisted delivery, odds ratio = 0.6, 95% CI 0.4 to 0.9 per week higher gestational age acceleration (p = .05)). There was no evidence of association for other parental and perinatal characteristics. Conclusions: The associations of higher maternal body mass index and larger birth size with greater gestational age acceleration may imply that maternal overweight and obesity is associated with more rapid development of the fetus in utero. The implications of gestational age acceleration for postnatal health warrant further investigation.

6.
Br J Sports Med ; 2018 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-29860237

RESUMO

Low energy availability (EA) is suspected to be the underlying cause of both the Female Athlete Triad and the more recently defined syndrome, Relative Energy Deficiency in Sport (RED-S). The International Olympic Committee (IOC) defined RED-S as a syndrome of health and performance impairments resulting from an energy deficit. While the importance of adequate EA is generally accepted, few studies have attempted to understand whether low EA is associated with the health and performance consequences posited by the IOC. OBJECTIVE: The purpose of this cross-sectional study was to examine the association of low EA with RED-S health and performance consequences in a large clinical population of female athletes. METHODS: One thousand female athletes (15-30 years) completed an online questionnaire and were classified as having low or adequate EA. The associations between low EA and the health and performance factors listed in the RED-S models were evaluated using chi-squared test and the odds ratios were evaluated using binomial logistic regression (p<0.05). RESULTS: Athletes with low EA were more likely to be classified as having increased risk of menstrual dysfunction, poor bone health, metabolic issues, haematological detriments, psychological disorders, cardiovascular impairment and gastrointestinal dysfunction than those with adequate EA. Performance variables associated with low EA included decreased training response, impaired judgement, decreased coordination, decreased concentration, irritability, depression and decreased endurance performance. CONCLUSION: These findings demonstrate that low EA measured using self-report questionnaires is strongly associated with many health and performance consequences proposed by the RED-S models.

7.
Stat Med ; 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29781174

RESUMO

Estimating velocity and acceleration trajectories allows novel inferences in the field of longitudinal data analysis, such as estimating change regions rather than change points, and testing group effects on nonlinear change in an outcome (ie, a nonlinear interaction). In this article, we develop derivative estimation for 2 standard approaches-polynomial mixed models and spline mixed models. We compare their performance with an established method-principal component analysis through conditional expectation through a simulation study. We then apply the methods to repeated blood pressure (BP) measurements in a UK cohort of pregnant women, where the goals of analysis are to (i) identify and estimate regions of BP change for each individual and (ii) investigate the association between parity and BP change at the population level. The penalized spline mixed model had the lowest bias in our simulation study, and we identified evidence for BP change regions in over 75% of pregnant women. Using mean velocity difference revealed differences in BP change between women in their first pregnancy compared with those who had at least 1 previous pregnancy. We recommend the use of penalized spline mixed models for derivative estimation in longitudinal data analysis.

8.
Int J Epidemiol ; 47(2): 516-525, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29462323

RESUMO

Background: DNA methylation levels are known to vary over time, and modelling these trajectories is crucial for our understanding of the biological relevance of these changes over time. However, due to the computational cost of fitting multilevel models across the epigenome, most trajectory modelling efforts to date have focused on a subset of CpG sites identified through epigenome-wide association studies (EWAS) at individual time-points. Methods: We propose using linear regression across the repeated measures, estimating cluster-robust standard errors using a sandwich estimator, as a less computationally intensive strategy than multilevel modelling. We compared these two longitudinal approaches, as well as three approaches based on EWAS (associated at baseline, at any time-point and at all time-points), for identifying epigenetic change over time related to an exposure using simulations and by applying them to blood DNA methylation profiles from the Accessible Resource for Integrated Epigenomics Studies (ARIES). Results: Restricting association testing to EWAS at baseline identified a less complete set of associations than performing EWAS at each time-point or applying the longitudinal modelling approaches to the full dataset. Linear regression models with cluster-robust standard errors identified similar sets of associations with almost identical estimates of effect as the multilevel models, while also being 74 times more efficient. Both longitudinal modelling approaches identified comparable sets of CpG sites in ARIES with an association with prenatal exposure to smoking (>70% agreement). Conclusions: Linear regression with cluster-robust standard errors is an appropriate and efficient approach for longitudinal analysis of DNA methylation data.

9.
Hum Mol Genet ; 27(7): 1301-1308, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29365106

RESUMO

Psychosocial adversity in childhood (e.g. abuse) and low socioeconomic position (SEP) can have significant lasting effects on social and health outcomes. DNA methylation-based biomarkers are highly correlated with chronological age; departures of methylation-predicted age from chronological age can be used to define a measure of age acceleration, which may represent a potential biological mechanism linking environmental exposures to later health outcomes. Using data from two cohorts of women Avon Longitudinal Study of Parents and Children, (ALSPAC), N = 989 and MRC National Survey of Health and Development, NSHD, N = 773), we assessed associations of SEP, psychosocial adversity in childhood (parental physical or mental illness or death, parental separation, parental absence, sub-optimal maternal bonding, sexual, emotional and physical abuse and neglect) and a cumulative score of these psychosocial adversity measures, with DNA methylation age acceleration in adulthood (measured in peripheral blood at mean chronological ages 29 and 47 in ALSPAC and buccal cells at age 53 in NSHD). Sexual abuse was strongly associated with age acceleration in ALSPAC (sexual abuse data were not available in NSHD), e.g. at the 47-year time point sexual abuse associated with a 3.41 years higher DNA methylation age (95% CI 1.53 to 5.29) after adjusting for childhood and adulthood SEP. No associations were observed between low SEP, any other psychosocial adversity measure or the cumulative psychosocial adversity score and age acceleration. DNA methylation age acceleration is associated with sexual abuse, suggesting a potential mechanism linking sexual abuse with adverse outcomes. Replication studies with larger sample sizes are warranted.

10.
BMJ Open ; 7(10): e016708, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29092899

RESUMO

OBJECTIVES: Our aim was to investigate the association of epigenetic age and physical capability in later life. Having a higher epigenetic than chronological age (known as age acceleration (AA)) has been found to be associated with an increased rate of mortality. Similarly, physical capability has been proposed as a marker of ageing due to its consistent associations with mortality. SETTING: The MRC National Survey of Health and Development (NSHD) cohort study. PARTICIPANTS: We used data from 790 women from the NSHD who had DNA methylation data available. DESIGN: Epigenetic age was calculated using buccal cell (n=790) and matched blood tissue (n=152) from 790 female NSHD participants. We investigated the association of AA at age 53 with changes in physical capability in women from ages 53 to 60-64. Regression models of change in each measure of physical capability on AA were conducted. Secondary analysis focused on the relationship between AA and smoking, alcohol, body mass index (BMI) and socioeconomic position. OUTCOME MEASURES: Three objective measures of physical capability were used: grip strength, standing balance time and chair rise speed. RESULTS: Epigenetic age was lower than chronological age (mean 53.4) for both blood (50.3) and buccal cells (42.8). AA from blood was associated with a greater decrease in grip strength from ages 53 to 60-64 (0.42 kg decrease per year of AA, 95% CI 0.03, 0.82 kg; p=0.03, n=152), but no associations were observed with standing balance time or chair rise speed. Current smoking and lower BMI were associated with lower epigenetic age from buccal cells. CONCLUSIONS: We found evidence that AA in blood is associated with a greater decrease in grip strength in British females aged between 53 and 60-64, but no association with standing balance time or chair rise speed was found.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigenômica , Força da Mão , Aptidão Física , Índice de Massa Corporal , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Pessoa de Meia-Idade , Mucosa Bucal , Equilíbrio Postural , Fumar , Fatores Socioeconômicos , Reino Unido
11.
Ann Hum Biol ; 44(8): 715-722, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29113497

RESUMO

BACKGROUND: Controlling for maturational status and timing is crucial in lifecourse epidemiology. One popular non-invasive measure of maturity is the age at peak height velocity (PHV). There are several ways to estimate age at PHV, but it is unclear which of these to use in practice. AIM: To find the optimal approach for estimating age at PHV. SUBJECTS AND METHODS: Methods included the Preece & Baines non-linear growth model, multi-level models with fractional polynomials, SuperImposition by Translation And Rotation (SITAR) and functional data analysis. These were compared through a simulation study and using data from a large cohort of adolescent boys from the Christ's Hospital School. RESULTS: The SITAR model gave close to unbiased estimates of age at PHV, but convergence issues arose when measurement error was large. Preece & Baines achieved close to unbiased estimates, but shares similarity with the data generation model for our simulation study and was also computationally inefficient, taking 24 hours to fit the data from Christ's Hospital School. Functional data analysis consistently converged, but had higher mean bias than SITAR. Almost all methods demonstrated strong correlations (r > 0.9) between true and estimated age at PHV. CONCLUSIONS: Both SITAR or the PBGM are useful models for adolescent growth and provide unbiased estimates of age at peak height velocity. Care should be taken as substantial bias and variance can occur with large measurement error.


Assuntos
Antropometria/métodos , Estatura , Crescimento , Adolescente , Fatores Etários , Criança , Estudos de Coortes , Humanos , Masculino , Modelos Biológicos , Adulto Jovem
12.
Clin Epigenetics ; 9: 100, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28932320

RESUMO

In this letter to the editor, we highlight some concerns with a recently published method to estimate gestational age at delivery from DNA methylation data. We conduct novel analyses to highlight the implications of different choices in study design and statistical methods for the prediction of phenotypes from methylation data.


Assuntos
Metilação de DNA , Idade Gestacional , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Modelos Estatísticos , Fenótipo , Gravidez , Projetos de Pesquisa
13.
BMJ Open ; 7(7): e013412, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-28751482

RESUMO

OBJECTIVES: Adult sagittal posture is established during childhood and adolescence. A flattened or hypercurved spine is associated with poorer musculoskeletal health in adulthood. Although anthropometry from birth onwards is expected to be a key influence on sagittal posture design, this has never been assessed during childhood. Our aim was to estimate the association between body size throughout childhood with sagittal postural patterns at age 7. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A subsample of 1029 girls and 1101 boys taking part in the 7-year-old follow-up of the birth cohort Generation XXI (Porto, Portugal) was included. We assessed the associations between anthropometric measurements (weight, height and body mass index) at birth, 4 and 7 years of age and postural patterns at age 7. Postural patterns were defined using latent profile analysis, a probabilistic model-based technique which allows for simultaneously including anthropometrics as predictors of latent profiles by means of logistic regression. RESULTS: Postural patterns identified were sway, flat and "neutral to hyperlordotic"in girls, and "sway to neutral", flat and hyperlordotic in boys; with flat and hyperlordotic postures representing a straightened and a rounded spine, respectively. In both girls and boys, higher weight was associated with lower odds of a flat pattern compared with a sway/"sway to neutral"pattern, with stronger associations at older ages: for example, ORs were 0.68 (95% CI 0.53 to 0.88) per SD increase in birth weight and 0.36 (95% CI 0.19 to 0.68) per SD increase in weight at age 7 in girls, with similar findings in boys. Boys with higher ponderal index at birth were more frequently assigned to the hyperlordotic pattern (OR=1.44 per SD; p=0.043). CONCLUSIONS: Our findings support a prospective sculpting role of body size and therefore of load on musculoskeletal spinopelvic structures, with stronger associations as children get older.


Assuntos
Antropometria , Peso ao Nascer , Postura , Coluna Vertebral/fisiopatologia , Fatores Etários , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Desenvolvimento Musculoesquelético , Portugal , Estudos Prospectivos
14.
Cancer Causes Control ; 28(8): 877-888, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28646365

RESUMO

PURPOSE: The insulin-like growth factor (IGF) system is modifiable by diet and lifestyle, and has been linked to prostate cancer development and progression. METHODS: We conducted a prospective cohort study of 621 men diagnosed with localized prostate cancer to investigate the associations of dietary and lifestyle changes with post-diagnosis circulating levels of IGF-I and IGFBP-3. We used analysis of covariance to estimate the associations, controlling for baseline IGF-I or IGFBP-3, respectively. RESULTS: Mean IGF-I levels were 6.5% (95% CI -12.8, -0.3%, p = 0.04) lower in men who decreased their protein intake after diagnosis compared to men who did not change. Men who changed their fruit and vegetable intake had lower IGF-I levels compared to non-changers [Decreased intake: -10.1%, 95% CI -18.4, -1.8%, p = 0.02; Increased intake: -12.0%, 95% CI -18.4, -1.8%, p = 0.002]. IGFBP-3 was 14.6% (95% CI -24.5, -4.8%, p = 0.004) lower in men who achieved a healthy body mass index after diagnosis. Men who became inactive had 9.5% higher average IGF-I levels (95% CI 0.1, 18.9%, p = 0.05). CONCLUSIONS: Decreased protein intake and body mass index, and increased physical activity and fruit and vegetable intake, following a prostate cancer diagnosis were associated with reduced post-diagnosis serum IGF-I and IGFBP-3. Counterintuitively, reduced fruit and vegetable intake was also associated with reduced IGF-I, but with weak statistical support, possibly implicating chance. If confirmed in other studies, our findings may inform potential lifestyle interventions in prostate cancer. ProtecT was registered at International Standard Randomised Controlled Trial Registry, http://isrctn.org as ISRCTN20141297.


Assuntos
Dieta , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Estilo de Vida , Neoplasias da Próstata/sangue , Idoso , Índice de Massa Corporal , Proteínas na Dieta , Exercício , Comportamento Alimentar , Frutas , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Verduras
15.
Int J Epidemiol ; 46(2): 549-558, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28089957

RESUMO

Background: Statistical models that use an individual's DNA methylation levels to estimate their age (known as epigenetic clocks) have recently been developed, with 96% correlation found between epigenetic and chronological age. We postulate that differences between estimated and actual age [age acceleration (AA)] can be used as a measure of developmental age in early life. Methods: We obtained DNA methylation measures at three time points (birth, age 7 years and age 17 years) in 1018 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Using an online calculator, we estimated epigenetic age, and thus AA, for each child at each time point. We then investigated whether AA was prospectively associated with repeated measures of height, weight, body mass index (BMI), bone mineral density, bone mass, fat mass, lean mass and Tanner stage. Results: Positive AA at birth was associated with higher average fat mass [1321 g per year of AA, 95% confidence interval (CI) 386, 2256 g] from birth to adolescence (i.e. from age 0-17 years) and AA at age 7 was associated with higher average height (0.23 cm per year of AA, 95% CI 0.04, 0.41 cm). Conflicting evidence for the role of AA (at birth and in childhood) on changes during development was also found, with higher AA being positively associated with changes in weight, BMI and Tanner stage, but negatively with changes in height and fat mass. Conclusions: We found evidence that being ahead of one's epigenetic age acceleration is related to developmental characteristics during childhood and adolescence. This demonstrates the potential for using AA as a measure of development in future research.


Assuntos
Índice de Massa Corporal , Tamanho Corporal , Densidade Óssea , Metilação de DNA , Epigênese Genética , Adolescente , Peso ao Nascer , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Estudos Longitudinais , Masculino , Modelos Estatísticos , Reino Unido
16.
PLoS One ; 11(11): e0167360, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27902751

RESUMO

BACKGROUND: Uncertainty remains about the true extent by which alcohol consumption causes a number of health outcomes. Genetic variants, or combinations of variants built into a polygenic risk score (PGRS), can be used in an instrumental variable framework to assess causality between a phenotype and disease outcome of interest, a method known as Mendelian randomisation (MR). We aimed to identify genetic variants involved in the aetiology of alcohol consumption, and develop a PGRS for alcohol. METHODS: Repeated measures of alcohol consumption from mothers and their offspring were collected as part of the Avon Longitudinal Study of Parents and Children. We tested the association between 89 SNPs (identified from either published GWAS data or from functional literature) and repeated measures of alcohol consumption, separately in mothers (from ages 28-48) and offspring (from ages 15-21) who had ever reported drinking. We modelled log units of alcohol using a linear mixed model and calculated beta coefficients for each SNP separately. Cross-validation was used to determine an allelic score for alcohol consumption, and the AVENGEME algorithm employed to estimate variance of the trait explained. RESULTS: Following correction for multiple testing, one SNP (rs1229984) showed evidence for association with alcohol consumption (ß = -0.177, SE = 0.042, p = <0.0001) in the mothers. No SNPs showed evidence for association in the offspring after correcting for multiple testing. The optimal allelic score was generated using p-value cut offs of 0.5 and 0.05 for the mothers and offspring respectively. These scores explained 0.3% and 0.7% of the variance. CONCLUSION: Our PGRS explains a modest amount of the variance in alcohol consumption and larger sample sizes would be required to use our PGRS in an MR framework.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Predisposição Genética para Doença , Adolescente , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
BJU Int ; 118(6): 911-918, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26799945

RESUMO

OBJECTIVE: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa). SUBJECTS AND METHODS: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. RESULTS: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. CONCLUSION: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies.


Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Europa (Continente) , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Reino Unido , Estados Unidos , Conduta Expectante
18.
Hum Mol Genet ; 25(1): 191-201, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26546615

RESUMO

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigênese Genética , Peso ao Nascer , Criança , Estudos de Coortes , Humanos , Estudos Longitudinais , Mães
19.
Stat Methods Med Res ; 25(5): 1875-1891, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-24108270

RESUMO

Serial measurements of prostate-specific antigen (PSA) are used as a biomarker for men diagnosed with prostate cancer following an active monitoring programme. Distinguishing pathological changes from natural age-related changes is not straightforward. Here, we compare four approaches to modelling age-related change in PSA with the aim of developing reference ranges for repeated measures of PSA. A suitable model for PSA reference ranges must satisfy two criteria. First, it must offer an accurate description of the trend of PSA on average and in individuals. Second, it must be able to make accurate predictions about new PSA observations for an individual and about the entire PSA trajectory for a new individual.


Assuntos
Envelhecimento/sangue , Antígeno Prostático Específico/sangue , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Valores de Referência
20.
J Clin Pathol ; 69(2): 171-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26500332

RESUMO

Vascular endothelial growth factor (VEGF) undergoes alternative splicing to produce both proangiogenic and antiangiogenic isoforms. Preferential splicing of proangiogenic VEGF is determined by serine-arginine protein kinase 1 (SRPK1), which is upregulated in a number of cancers. In the present study, we aimed to investigate SRPK1 expression in prostate cancer (PCa) and its association with cancer progression. SRPK1 expression was assessed using immunohistochemistry of PCa tissue extracted from radical prostatectomy specimens of 110 patients. SRPK1 expression was significantly higher in tumour compared with benign tissue (p<0.00001) and correlated with higher pT stage (p=0.004), extracapsular extension (p=0.003) and extracapsular perineural invasion (p=0.008). Interestingly, the expression did not correlate with Gleason grade (p=0.21), suggesting that SRPK1 facilitates the development of a tumour microenvironment that favours growth and invasion (possibly through stimulating angiogenesis) while having little bearing on the morphology or function of the tumour cells themselves.


Assuntos
Proteínas Angiogênicas/análise , Biomarcadores Tumorais/análise , Neoplasias da Próstata/enzimologia , Proteínas Serina-Treonina Quinases/análise , Adulto , Idoso , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Microambiente Tumoral , Regulação para Cima
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