Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 184
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31607674

RESUMO

OBJECTIVES: This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. BACKGROUND: Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. METHODS: Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. RESULTS: Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p < 0.001), whereas fat mass was negatively associated with cIMT (difference: -0.0032; 95% CI: 0.004 to -0.001; p = 0.001). Similar results were obtained when investigating cumulative exposure to these factors throughout adolescence. An increase in cIMT maintained circumferential wall stress in the face of increased mean arterial pressure when increases in body mass were attributable to increased FFM, but not fat mass. Risk factor-associated differences in the radial artery occurred in the media alone, and there was little evidence of a relationship between intimal thickness and any risk factor. CONCLUSIONS: Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures might be more appropriate for the identification of arterial disease before adulthood.

2.
Eur J Endocrinol ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325907

RESUMO

OBJECTIVE: The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). DESIGN AND METHODS: Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). RESULTS: In the two prospective nested case-control studies, logistic regression adjusting for sex, age, body mass index, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR 1.28 per 1 SD higher cortisol, 95% CI 1.06-1.54). In the meta-analysis of prospective studies the equivalent result was OR 1.18, 95% CI 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR 1.06, 95% CI 0.98-1.15. CONCLUSIONS: All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.

3.
JAMA Netw Open ; 2(6): e196587, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31251383

RESUMO

Importance: Less favorable trajectories of depressive mood from adolescence to early adulthood are associated with current and later psychopathology, impaired educational attainment, and social dysfunction, yet the genetic and environmental risk factors associated with these trajectories are not fully established. Examining what risk factors are associated with different trajectories of depressive mood could help identify the nature of depression symptoms and improve preventive interventions for those at most risk. Objective: To examine the differential associations of genetic and environmental risk factors with trajectories of depression symptoms among individuals observed from ages 10 to 24 years. Design, Setting, and Participants: In a longitudinal cohort study established in 1990 and currently ongoing (the Avon Longitudinal Study of Parents and Children [ALSPAC]), growth mixture modeling was used to identify trajectories of depression symptoms in 9394 individuals in the United Kingdom. Associations of different risk factors with these trajectories were then examined. Analysis was conducted between August 2018 and January 2019. Main Outcomes and Measures: Trajectories were composed from depression symptoms measured using the Short Mood and Feelings Questionnaire at 9 occasions from ages 10 to 24 years. Risk factors included sex, a polygenic risk score taken from a recent genome-wide association study of depression symptoms, maternal postnatal depression, partner cruelty to the offspring's mother when the child was aged 2 to 4 years, childhood anxiety at age 8 years, and being bullied at age 10 years. Results: Data on all risk factors, confounders, and the outcome were available for 3525 individuals, including 1771 (50.2%) who were female. Trajectories were assessed between the mean (SD) age of 10.7 (0.3) years and mean (SD) age of 23.8 (0.5) years. Overall, 5 distinct trajectories of depression symptoms were identified: (1) stable low (2506 individuals [71.1%]), (2) adolescent limited (325 individuals [9.2%]), (3) childhood limited (203 individuals [5.8%]), (4) early-adult onset (393 individuals [11.1%]), and (5) childhood persistent (98 individuals [2.8%]). Of all the associations of risk factors with trajectories, sex (odds ratio [OR], 6.45; 95% CI, 2.89-14.38), the polygenic risk score for depression symptoms (OR, 1.47; 95% CI, 1.10-1.96), and childhood anxiety (OR, 1.30; 95% CI, 1.16-1.45) showed the strongest association with the childhood-persistent trajectory of depression symptoms compared with the stable-low trajectory. Maternal postnatal depression (OR, 2.39; 95% CI, 1.41-4.07) had the strongest association with the early-adult-onset trajectory, while partner cruelty to mother (OR, 2.30; 95% CI, 1.36-3.90) had the strongest association with the adolescent-limited trajectory. Bullying (OR, 8.08; 95% CI, 4.92-13.26) showed the strongest association with the childhood-limited trajectory. Conclusions and Relevance: The least favorable trajectories of depression symptoms (childhood persistent and early-adult onset) were associated with both genetic and environmental risk factors, but the 2 trajectories of limited duration that had resolved by early adulthood (childhood limited and adolescent limited) were not associated with the polygenic risk score or maternal postnatal depression. Bullying was strongly associated with both the childhood-persistent and childhood-limited trajectories, suggesting that this risk factor may have a time-specific effect. These findings suggest that examining genetic and multiple time-specific environmental antecedents could help identify trajectories of varying onset and chronicity.

4.
PLoS One ; 14(6): e0218549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220183

RESUMO

INTRODUCTION: It is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research. OBJECTIVES: We quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples. METHODS: In the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (<6 months) and long-term (>3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements. RESULTS: Both fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66. CONCLUSION: Technical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.

5.
Nat Commun ; 10(1): 2773, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235808

RESUMO

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.


Assuntos
Cárie Dentária/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Periodontite/genética , Cárie Dentária/epidemiologia , Genômica , Hereditariedade , Humanos , Análise da Randomização Mendeliana , Periodontite/epidemiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Autorrelato/estatística & dados numéricos
6.
Lancet Child Adolesc Health ; 3(7): 474-481, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31126896

RESUMO

BACKGROUND: The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors. METHODS: We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had detailed adiposity measurements between the ages 9-17 years and arterial stiffness (carotid to femoral pulse wave velocity [PWV]) measured at age 17 years. Body-mass index (BMI) and waist-to-height ratio were calculated from weight, height, and waist circumference measurements whereas fat mass was assessed using repeated dual-energy x-ray absorptiometry (DEXA) scans. We used total and trunk fat mass indices (FMIs) to classify participants as normal (<75th percentile) or high (>75th percentile) FMI. We classified participants as being metabolically unhealthy if they had three or more of the following risk factors: high levels of systolic blood pressure, triglycerides, or glucose (all >75th percentile) or low levels of high-density lipoprotein (<25th percentile). We used multivariable linear regression analysis to assess the relationship between PWV and exposure to adiposity, and tested for linear trend of PVW levels across ordinal groups. We used latent class growth mixture modelling analysis to assess the effect of longitudinal changes in adiposity indices through adolescence on arterial stiffness. FINDINGS: We studied 3423 participants (1866 [54·5%] female and 1557 [45·5%] male). Total fat mass was positively associated with PWV at age 17 years (0·004 m/s per kg, 95% CI 0·001-0·006; p=0·0081). Persistently high total FMI and trunk FMI between ages 9 and 17 years were related to greater PWV (0·15 m/s per kg/m2, 0·05-0·24; p=0·0044 and 0·15 m/s per kg/m2, 0·06-0·25; p=0·0021) compared with lower FMI. Metabolic abnormalities amplified the adverse effect of high total FMI on arterial stiffness (PWV 6·0 m/s [95% CI 5·9-6·0] for metabolically healthy participants and 6·2 m/s [5·9-6·4] for metabolically unhealthy participants). Participants who restored normal total FMI in adolescence (PWV 5·8 m/s [5·7-5·9] for metabolically healthy and 5·9 m/s [5·6-6·1] for metabolically unhealthy) had comparable PWV to those who had normal FMI throughout (5·7 m/s [5·7-5·8] for metabolically healthy and 5·9 m/s [5·8-5·9] for metabolically unhealthy). INTERPRETATION: Persistently high fat mass during adolescence was associated with greater arterial stiffness and was further aggravated by an unfavourable metabolic profile. Reverting to normal FMI in adolescence was associated with normal PWV, suggesting adolescence as an important period for interventions to tackle obesity in the young to maximise long-term vascular health. FUNDING: UK Medical Research Council, Wellcome Trust, British Heart Foundation, and AFA Insurances.

7.
Cell ; 177(3): 587-596.e9, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31002795

RESUMO

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.

10.
Nat Commun ; 10(1): 1052, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837455

RESUMO

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.


Assuntos
Loci Gênicos/imunologia , Predisposição Genética para Doença , Fatores Imunológicos/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Adulto , Idoso , Estudos de Coortes , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Imunológicos/imunologia , Masculino , Pessoa de Meia-Idade , Úlceras Orais/imunologia , Estomatite Aftosa/imunologia , Linfócitos T/imunologia
11.
Drug Alcohol Depend ; 197: 344-353, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30827758

RESUMO

BACKGROUND: High levels of alcohol use in pregnancy have been shown to be associated with negative physical health consequences in offspring. However, the literature is less clear on the association of alcohol use in pregnancy and offspring mental health, specifically for low levels of prenatal alcohol exposure. We conducted a systematic review to evaluate studies examining this association. METHODS: Studies were identified by searching PsycINFO, PubMed and Web of Science, and were included if they examined alcohol use during pregnancy as an exposure and offspring mental health at age 3 or older as an outcome. We excluded non-English language publications and studies of fetal alcohol syndrome. RESULTS: Thirty-three studies were included and were categorized by mental health outcomes: anxiety/depression, emotional problems, total internalizing problems, total problem score, and conduct disorder. Over half of the analyses reported a positive association of prenatal alcohol exposure and offspring mental health problems. CONCLUSIONS: Our review suggests that maternal alcohol use during pregnancy is associated with offspring mental health problems, even at low to moderate levels of alcohol use. Future investigation using methods that allow stronger causal inference is needed to further investigate if these associations shown are causal.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Alcoolismo/psicologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Pré-Escolar , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
12.
J Youth Adolesc ; 48(4): 815-827, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30671716

RESUMO

Depression is a common mental illness and research has focused on late childhood and adolescence in an attempt to prevent or reduce later psychopathology and/or social impairments. It is important to establish and study population-averaged trajectories of depressive symptoms across adolescence as this could characterise specific changes in populations and help identify critical points to intervene with treatment. Multilevel growth-curve models were used to explore adolescent trajectories of depressive symptoms in 9301 individuals (57% female) from the Avon Longitudinal Study of Parents and Children, a UK based pregnancy cohort. Trajectories of depressive symptoms were constructed for males and females using the short mood and feelings questionnaire over 8 occasions, between 10 and 22 years old. Critical points of development such as age of peak velocity for depressive symptoms (the age at which depressive symptoms increase most rapidly) and the age of maximum depressive symptoms were also derived. The results suggested that from similar initial levels of depressive symptoms at age 11, females on average experienced steeper increases in depressive symptoms than males over their teenage and adolescent years until around the age of 20 when levels of depressive symptoms plateaued and started to decrease for both sexes. Females on average also had an earlier age of peak velocity of depressive symptoms that occurred at 13.5 years, compared to males who on average had an age of peak velocity at 16 years old. Evidence was less clear for a difference between the ages of maximum depressive symptoms which were on average 19.6 years for females and 20.4 for males. Identifying critical periods for different population subgroups may provide useful knowledge for treating and preventing depression and could be tailored to be time specific for certain groups. Possible explanations and recommendations are discussed.


Assuntos
Depressão/epidemiologia , Adolescente , Adulto , Criança , Feminino , Gráficos de Crescimento , Humanos , Estudos Longitudinais , Masculino , Gravidez , Inquéritos e Questionários , Reino Unido/epidemiologia , Adulto Jovem
13.
Circulation ; 138(20): 2187-2201, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30524135

RESUMO

Background: Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages - nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, whilst maintaining statistical power and ability for causal inference. Methods: In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR) and sub-sample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 (N=1420-3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 (N=386-418). Results: In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure (BP) and left ventricular mass index (LVMI) in young adults (e.g., difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87x10-06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (SV: difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO: difference per 3.58kg/m2: 0.11l/min/m1.83; 95% CI: 0.03, 0.19; P=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate. Conclusions: Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. Higher BMI also resulted in increased CO in the RbG study, which appeared to be solely driven by SV, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using RbG.

14.
J Am Coll Cardiol ; 72(24): 3142-3154, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30545453

RESUMO

BACKGROUND: Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. OBJECTIVES: The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. METHODS: BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. RESULTS: Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. CONCLUSIONS: The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects.


Assuntos
Adiposidade , Índice de Massa Corporal , Doença das Coronárias/etiologia , Metabolômica , Absorciometria de Fóton , Adolescente , Pressão Sanguínea , Proteína C-Reativa/metabolismo , Criança , Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/fisiopatologia , Feminino , Humanos , Insulina/sangue , Estudos Longitudinais , Masculino , Triglicerídeos/sangue
15.
Wellcome Open Res ; 3: 49, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30467552

RESUMO

Antibodies against pathogens provide information on exposure to infectious agents and are meaningful measures of past and present infection. Antibodies were measured in the plasma of children that are the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Plasma was collected during clinics at age 5, 7, 11 and 15 years. The antigens examined include: fungal ( Saccharomyces cerevisiae); protozoan ( Toxoplasma gondii and surface antigen 1 of  T. gondii); herpes viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1); common colds (influenza virus subtypes H1N1 and H3N2); other antigens (measles); animal (feline herpes virus, Theiler's virus); bacteria ( Helicobacter pylori); dietary antigens (bovine casein alpha protein, bovine casein beta protein). Alongside the depth of data available within the ALSPAC cohort, this longitudinal resource will enable the investigation of the association between infections and a wide variety of outcomes.

16.
Wellcome Open Res ; 3: 65, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30345375

RESUMO

Background: The FUT2 (fucosyltransferase 2) gene encodes alpha (1,2) fucosyltransferase, which determines blood group secretor status. Being homozygous for the inactive "non-secretor" rs601338(A) allele appears to confer resistance to certain infections (e.g. Norovirus, Rotavirus and Helicobacter pylori) and susceptibility to others (e.g. Haemophilus influenza and Streptococcus pneumonia). Non-secretors also have an increased risk of type 1 diabetes and inflammatory bowel disease. We aimed to determine the association of the FUT2 secretor genotype with infections and chronic conditions in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Methods: This study included 7,582 pregnant women from the ALSPAC pregnancy cohort. Personal history of infections (measles, mumps, chicken pox, whooping cough, cold sores, meningitis, genital herpes, gonorrhea and urinary infections) and chronic conditions (kidney disease, hypertension, diabetes, rheumatism, arthritis, psoriasis, hay fever, asthma, eczema and various allergies) were self-reported by standardized questionnaire. FUT2 secretor status was determined from the rs601338 genotype. Results: Overall, 1920 women (25.3%) were homozygous for the FUT2 non-secretor allele (AA). Secretor status was associated with mumps, with 68% of non-secretors experiencing this infection, compared to 48% of secretors (RR, 1.40; 95% CI, 1.34-1.46; p<0.0001). A weaker association was observed for measles infection (76% vs. 72%; RR, 1.05; 95% CI, 1.02-1.09; p=0.0008). Non-secretors also experienced a 39% increased risk of kidney disease (5.4% vs. 3.9%; RR, 1.39; 95% CI, 1.11-1.75; p=0.004). For some conditions, including gonorrhea and arthritis, FUT2 heterozygosity (GA) appeared to confer an intermediate phenotype. There was no strong evidence of association between FUT2 secretor status and other infections or chronic conditions, although statistical power was limited for rare outcomes. Conclusion: Our results identify an association between FUT2 secretor status and kidney disease, and confirm a recently reported association with susceptibility to mumps infection. The clinical implications of these associations warrant further investigation.

17.
Obesity (Silver Spring) ; 26(11): 1796-1806, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30358150

RESUMO

OBJECTIVE: The aim of this study was to obtain estimates of the causal relationship between BMI and mortality. METHODS: Mendelian randomization (MR) with BMI-associated genotypic variation was used to test the causal effect of BMI on all-cause and cause-specific mortality in UK Biobank participants of White British ancestry. RESULTS: MR analyses supported a causal association between higher BMI and greater risk of all-cause mortality (hazard ratio [HR] per 1 kg/m2 : 1.03; 95% CI: 0.99-1.07) and mortality from cardiovascular diseases (HR: 1.10; 95% CI: 1.01-1.19), specifically coronary heart disease (HR: 1.12; 95% CI: 1.00-1.25) and those excluding coronary heart disease/stroke/aortic aneurysm (HR: 1.24; 95% CI: 1.03-1.48), stomach cancer (HR: 1.18; 95% CI: 0.87-1.62), and esophageal cancer (HR: 1.22; 95% CI: 0.98-1.53), and a decreased risk of lung cancer mortality (HR: 0.96; 95% CI: 0.85-1.08). Sex stratification supported the causal role of higher BMI increasing bladder cancer mortality risk (males) but decreasing respiratory disease mortality risk (males). The J-shaped observational association between BMI and mortality was visible with MR analyses, but the BMI at which mortality was minimized was lower and the association was flatter over a larger BMI range. CONCLUSIONS: Results support a causal role of higher BMI in increasing the risk of all-cause mortality and mortality from several specific causes.

18.
Circ Genom Precis Med ; 11(8): e001947, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30354344

RESUMO

In genotype-based recall (GBR) studies, people (or their biological samples) who carry genotypes of special interest for a given hypothesis test are recalled from a larger cohort (or biobank) for more detailed investigations. There are several GBR study designs that offer a range of powerful options to elucidate (1) genotype-phenotype associations (by increasing the efficiency of genetic association studies, thereby allowing bespoke phenotyping in relatively small cohorts), (2) the effects of environmental exposures (within the Mendelian randomization framework), and (3) gene-treatment interactions (within the setting of GBR interventional trials). In this review, we overview the literature on GBR studies as applied to cardiometabolic health outcomes. We also review the GBR approaches used to date and outline new methods and study designs that might enhance the utility of GBR-focused studies. Specifically, we highlight how GBR methods have the potential to augment randomized controlled trials, providing an alternative application for the now increasingly accepted Mendelian randomization methods usually applied to large-scale population-based data sets. Further to this, we consider how functional and basic science approaches alongside GBR designs offer intellectually intriguing and potentially powerful ways to explore the implications of alterations to specific (and potentially druggable) biological pathways.

19.
Hum Mol Genet ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30215712

RESUMO

Smoking usually begins in adolescence, and early onset of smoking has been linked to increased risk of later life disease. There is a need to better understand the biological impact of cigarette smoking behaviours in adolescence. DNA methylation profiles related to smoking behaviours and cessation in adulthood have been previously identified, but alterations arising from smoking initiation have not been thoroughly investigated.We aimed to investigate DNA methylation in the Avon Longitudinal Study of Parents and Children in relation to: 1) different smoking measures; 2) time since smoking initiation and frequency of smoke exposure; and 3) latent classes of smoking behaviour.Using 2,620 CpG sites previously associated with cigarette smoking, we investigated DNA methylation change in relation to own smoking measures, smoke exposure duration and frequency, and using longitudinal latent class analysis between different smoking behaviour patterns in 968 adolescents.Eleven CpG sites located in seven gene regions were differentially methylated in relation to smoking in adolescence. While only AHRR (cg05575921) showed a robust consistent pattern of methylation in relation to weekly smoking, several CpGs showed differences in methylation among individuals who had tried smoking compared with non-smokers. In relation to smoke exposure duration and frequency, cg05575921 showed a strong dose-response relationship, while there was evidence for more immediate methylation change at other sites.Our findings illustrate the impact of cigarette smoking behaviours on DNA methylation at some smoking-responsive CpG sites, even among individuals with a short smoking history.

20.
BMJ ; 362: k3788, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254091

RESUMO

OBJECTIVES: To investigate whether the association between subjective wellbeing (subjective happiness and life satisfaction) and cardiometabolic health is causal. DESIGN: Two sample, bidirectional mendelian randomisation study. SETTING: Genetic data taken from various cohorts comprised of the general population (mostly individuals of European ancestry, plus a small proportion of other ancestries); follow-up analysis included individuals from the United Kingdom. PARTICIPANTS: Summary data were used from previous genome wide association studies (number of participants ranging from 83 198 to 339 224), which investigated traits related to cardiovascular or metabolic health, had the largest sample sizes, and consisted of the most similar populations while minimising sample overlap. A follow-up analysis included 337 112 individuals from the UK Biobank (54% female (n=181 363), mean age 56.87 years (standard deviation 8.00) at recruitment). MAIN OUTCOME MEASURES: Subjective wellbeing and 11 measures of cardiometabolic health (coronary artery disease; myocardial infarction; total, high density lipoprotein, and low density lipoprotein cholesterol; diastolic and systolic blood pressure; body fat; waist to hip ratio; waist circumference; and body mass index). RESULTS: Evidence of a causal effect of body mass index on subjective wellbeing was seen; each 1 kg/m2 increase in body mass index caused a -0.045 (95% confidence interval -0.084 to -0.006, P=0.02) standard deviation reduction in subjective wellbeing. Follow-up analysis of this association in an independent sample from the UK Biobank provided strong evidence of an effect of body mass index on satisfaction with health (ß=-0.035 unit decrease in health satisfaction (95% confidence interval -0.043 to -0.027) per standard deviation increase in body mass index, P<0.001). No clear evidence of a causal effect was seen between subjective wellbeing and the other cardiometabolic health measures, in either direction. CONCLUSIONS: These results suggest that a higher body mass index is associated with a lower subjective wellbeing. A follow-up analysis confirmed this finding, suggesting that the effect in middle aged people could be driven by satisfaction with health. Body mass index is a modifiable determinant, and therefore, this study provides further motivation to tackle the obesity epidemic because of the knock-on effects of higher body mass index on subjective wellbeing.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA