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1.
BMJ Open ; 12(1): e047748, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017230

RESUMO

OBJECTIVES: To explore clinically important increases in depression/anxiety from before to during the first UK COVID-19 lockdown and factors related to this change, with a particular focus on ethnic differences. DESIGN: Pre-COVID-19 and lockdown surveys nested within two longitudinal Born in Bradford cohort studies. PARTICIPANTS: 1860 mothers with a child aged 0-5 or 9-13, 48% Pakistani heritage. MAIN OUTCOME MEASURES: ORs for a clinically important increase (5 points or more) in depression (eight item Patient Health Questionnaire (PHQ-8)) and anxiety (Generalised Anxiety Disorder Assessment (GAD-7)) in unadjusted regression analyses, repeated with exposures of interest separated by ethnicity to look for differences in magnitude of associations, and lived experience of mothers captured in open text questions. RESULTS: The number of women reporting clinically important depression/anxiety increased from 11% to 20% (95% CI 10%-13%; 18%-22%) and from 10% to 16% (95% CI 8%-11%; 15%-18%), respectively. Increases in depression/anxiety were associated with loneliness (OR=8.37, 95% CI 5.70 to 12.27; 8.50, 95% CI 5.71 to 12.65, respectively); financial (6.23, 95% CI 3.96 to 9.80; 6.03, 95% CI 3.82 to 9.51), food (3.33, 95% CI 2.09 to 5.28; 3.46, 95% CI 2.15 to 5.58) and housing insecurity (3.29, 95% CI 2.36 to 4.58; 3.0, 95% CI 2.11 to 4.25); a lack of physical activity (3.13, 95% CI 2.15 to 4.56; 2.55, 95% CI 1.72 to 3.78); and a poor partner relationship (3.6, 95% CI 2.44 to 5.43; 5.1, 95% CI 3.37 to 7.62). The magnitude of associations between key exposures and worsening mental health varied between ethnic groups.Responses to open text questions illustrated a complex interplay of challenges contributing to mental ill health including: acute health anxieties; the mental load of managing multiple responsibilities; loss of social support and coping strategies; pressures of financial and employment insecurity; and being unable to switch off from the pandemic. CONCLUSIONS: Mental ill health has worsened for many during the COVID-19 lockdown, particularly in those who are lonely and economically insecure. The magnitude of associations between key exposures and worsening mental health varied between ethnic groups. Mental health problems may have longer term consequences for public health and interventions that address the potential causes are needed.


Assuntos
COVID-19 , Saúde Mental , Ansiedade/epidemiologia , Criança , Controle de Doenças Transmissíveis , Depressão/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Mães , SARS-CoV-2 , Reino Unido
2.
PLoS Genet ; 18(1): e1009887, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35061662

RESUMO

Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10-8) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to investigate other potentially modifiable intermediates.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34897472

RESUMO

CONTEXT: Excessive birth weight is associated with maternal and neonatal complications. However, ultrasonically estimated large for gestational age (LGA; >90th percentile) predicts these complications poorly. OBJECTIVE: To determine whether a maternal serum metabolite ratio developed for fetal growth restriction (FGR) is predictive of birth weight across the whole range, including LGA at birth. METHODS: Metabolites were measured using ultrahigh performance liquid chromatography-tandem mass spectroscopy. The 4-metabolite ratio was previously derived from an analysis of FGR cases and a random subcohort from the Pregnancy Outcome Prediction study. Here, we evaluated its relationship at 36 weeks of gestational age (wkGA) with birth weight in the subcohort (n = 281). External validation in the Born in Bradford (BiB) study (n = 2366) used the metabolite ratio at 24 to 28 wkGA. RESULTS: The inverse of the metabolite ratio at 36 wkGA predicted LGA at term [the area under the receiver operating characteristic curve (AUROCC) = 0.82, 95% CI 0.73 to 0.91, P = 6.7 × 10-5]. The ratio was also inversely associated with birth weight z score (linear regression, beta = -0.29 SD, P = 2.1 × 10-8). Analysis in the BiB cohort confirmed that the ratio at 24 to 28 wkGA predicted LGA (AUROCC = 0.60, 95% CI 0.54 to 0.67, P = 8.6 × 10-5) and was inversely associated with birth weight z score (beta = -0.12 SD, P = 1.3 × 10-9). CONCLUSIONS: A metabolite ratio which is strongly predictive of FGR is equally predictive of LGA birth weight and is inversely associated with birth weight across the whole range.

5.
Hum Mol Genet ; 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34897462

RESUMO

BACKGROUND: Higher birthweight is associated with higher adult BMI. Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favourable adiposity alleles on birthweight is unknown. Aim We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favourable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. METHODS: We used published GWAS data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favourable adult adiposity or BMI. We combined summary data across SNPs with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. RESULTS: Fetal genetic predisposition to higher metabolically favourable adult adiposity and higher adult BMI were both associated with higher birthweight (3grams per effect allele (95%CI, 1 to 5) averaged over 14 SNPs; p = 0.002; 0.5grams per effect allele (95%CI, 0 to 1) averaged over 76 SNPs; p = 0.042, respectively). SNPs with greater effects on metabolically favourable adiposity tended to have greater effects on birthweight (R2 = 0.2912, p = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, p = 0.602). CONCLUSIONS: Fetal genetic predisposition to both higher adult metabolically favourable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favourable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

6.
J Bone Miner Res ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34738659

RESUMO

Romosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (ß 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (ß -0.20; CI -0.38, -0.02), HDL cholesterol (ß -0.05; CI -0.10, -0.01), and apolipoprotein A-I (ß -0.05; CI -0.08, -0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow-up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

7.
BMC Cardiovasc Disord ; 21(1): 549, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34798837

RESUMO

BACKGROUND: Our aim was to comprehensively review published evidence on the association between having a congenital heart disease (CHD) compared with not, on educational attainment (i.e. not obtaining a university degree, completing secondary education, or completing any vocational training vs. obtaining/completing) in adults. METHOD: Studies were eligible if they reported the rate, odds, or proportion of level of educational attainment in adults by whether or not they had a CHD. RESULT: Out of 1537 articles screened, we identified 11 (N = 104,585 participants, 10,487 with CHD), 10 (N = 167,470 participants, 11,820 with CHD), and 8 (N = 150,813 participants, 9817 with CHD) studies reporting information on university education, secondary education, and vocational training, respectively in both CHD and non-CHD participants. Compared to their non-CHD peers, CHD patients were more likely not to obtain a university degree (OR = 1.38, 95% CI [1.16, 1.65]), complete secondary education (OR = 1.33, 95% CI [1.09, 1.61]) or vocational training (OR = 1.11, 95% CI [0.98, 1.26]). For all three outcomes there was evidence of between study heterogeneity, with geographical area contributing to this heterogeneity. CONCLUSION: This systematic review identified all available published data on educational attainment in CHD patients. Despite broad inclusion criteria we identified relatively few studies that included a comparison group from the same population, and amongst those that did, few adjusted for key confounders. Pooled analyses suggest evidence of lower levels of educational attainment in patients with CHD when compared to non-CHD peers. The extent to which this may be explained by confounding factors, such as parental education, or mediated by treatments is not possible to discern from the current research literature.

8.
Lancet Reg Health Eur ; 10: 100206, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34806068

RESUMO

Background: The importance of the maternal-infant dyad in the genesis of nonalcoholic fatty liver disease (NAFLD) is of increasing interest. The Avon Longitudinal Study of Parents and Children (ALSPAC) showed that at age 24, 1 in 5 had NAFLD measured by transient elastography and controlled attenuation parameter (CAP). Our aim was to investigate the association between breastfeeding duration and maternal pre-pregnancy BMI on offspring NAFLD in young adulthood. Methods: 4021 participants attended clinic for FibroScan and CAP measurement using Echosens 502 Touch®. 440 participants with Alcohol Use Disorders were excluded. Offspring of 100 non-singleton pregnancies were excluded. 2961 valid CAP measurements for NAFLD were analysed. Exposures of interest were breastfeeding of any duration, ≥6months exclusive breastfeeding, and maternal pre-pregnancy BMI. Multivariable regression models estimated the odds of NAFLD at 24 years. We performed a paternal negative control test to explore residual confounding in the analyses of pre-pregnancy BMI. Findings: There was a modest inverse association of exclusive and non-exclusive breastfeeding ≥6 months having a protective effect on NAFLD in offspring (OR 0·92 [95%CI 0·66-1·27] and OR 0·90 [0·67-1·21] respectively).The odds of offspring NAFLD in overweight pre-pregnancy maternal BMI and paternal BMI was OR 2·09 [1·62-2·68] and OR 1·33 [95%CI 1·07-1·65] respectively, with the ratio of effect sizes OR 1·57 [1·11-2·22]. Similarly, odds of offspring NAFLD with obese pre-pregnancy maternal BMI and paternal BMI was OR 2·66 [1·71-4·14] and OR 1·35 [0·91-2·00] respectively, with the ratio of effect sizes OR 1·98 [1·05-3·74]. Interpretation: Higher maternal pre-pregnancy BMI was associated with offspring NAFLD, having accounted for shared parental confounding. We did not replicate previous work that found a strong association between breastfeeding and NAFLD. Funding: Medical Research Council UK, Alcohol Research UK, David Telling Charitable Trust.

9.
Sci Rep ; 11(1): 21587, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732718

RESUMO

Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles. Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were - 0.03 (95% CI - 0.14, 0.08) and 0.01 (95% CI - 0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01-0.37 and interquartile range 0.10-0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95% CI 0.22, 0.52), omega-3 fatty acids (0.32, 95% CI 0.20, 0.43) histidine (0.32, 95% CI 0.23, 0.41) and pyruvate (0.32, 95% CI 0.22, 0.43). Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile.

10.
Nat Commun ; 12(1): 6120, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675202

RESUMO

Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target's expression or function, as a tool to anticipate the effect of drug action on the same target. Here we apply MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with blood lipids (HDL-C, LDL-C and triglycerides), we robustly prioritize 30 targets that might elicit beneficial effects in the prevention or treatment of CHD, including NPC1L1 and PCSK9, the targets of drugs used in CHD prevention. We discuss how this approach can be generalized to other targets, disease biomarkers and endpoints to help prioritize and validate targets during the drug development process.

11.
JAMA Netw Open ; 4(10): e2131683, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34709386

RESUMO

Importance: Although use of epidural analgesia during labor is safe, detailed information about its association with neonatal and child outcomes is limited. Objective: To investigate the association of labor epidural analgesia with neonatal outcomes and childhood development during the first 1000 days of life. Design, Setting, and Participants: This population-based cohort study used Scottish National Health Service hospital administrative data of all 435 281 singleton live births in Scotland between January 1, 2007, and December 31, 2016, with follow-up over the first 1000 days of life. All 435 281 mother-infant pairs delivering between 24 weeks 0 days and 43 weeks 6 days' gestation who were in active labor with cephalic presentation and who delivered vaginally or via unplanned cesarean delivery were included. Stillbirths and infants with known congenital anomalies were excluded. Data were analyzed between August 1, 2020, and July 23, 2021. Exposures: Epidural analgesia in labor. Main Outcomes and Measures: Neonatal outcomes included resuscitation, Apgar score less than 7 at 5 minutes, and neonatal unit admission. Childhood development measures (gross and fine motor function, communication, and social functioning) were obtained from standardized national childhood surveillance assessments performed at 2 years. Results: This study included a total of 435 281 live births with cephalic presentation in labor (median gestational age at delivery, 40 weeks [IQR, 39-41 weeks]; 221 153 male infants [50.8%]), of which 94 323 (21.7%) had labor epidural. Epidural analgesia was associated with a reduction in spontaneous vaginal deliveries (confounder-adjusted [Cadj] relative risk [RR], 0.46; 95% CI, 0.42-0.50), an increased risk of neonatal resuscitation (Cadj RR, 1.07; 95% CI, 1.03-1.11), and an increased risk of neonatal unit admission (Cadj RR, 1.14; 95% CI, 1.11-1.17). With additional analysis for mediation by mode of delivery (CMadj), these associations were reversed (CMadj RR, 0.83; 95% CI, 0.79-0.86 for neonatal resuscitation and CMadj RR, 0.94; 95% CI, 0.91-0.97 for neonatal unit admission). Epidural analgesia was associated with a reduced risk of an Apgar score less than 7 at 5 minutes in both confounder and confounder/mediation analyses. Epidural analgesia was associated with a reduced risk of having developmental concern in any domain at 2 years in confounder and confounder/mediation analyses (CMadj RR, 0.96; 95% CI, 0.93-0.98), with specifically fewer concerns regarding communication (CMadj RR, 0.96; 95% CI, 0.93-0.99) and fine motor skills (CMadj RR, 0.89; 95% CI, 0.82-0.97). Conclusions and Relevance: The results of this cohort study suggest that labor epidural analgesia is not independently associated with adverse neonatal or childhood development outcomes. Associations with neonatal resuscitation and admission were likely mediated by mode of delivery.

12.
Hum Reprod ; 36(12): 3141-3151, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34668019

RESUMO

STUDY QUESTION: What is the association between BMI and subfertility? SUMMARY ANSWER: We observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis. WHAT IS KNOWN ALREADY: High BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Cohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months). MAIN RESULTS AND THE ROLE OF CHANCE: Our findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI <20.0 kg/m2. A 1 kg/m2 higher genetically predicted BMI was linked to 26% greater odds of subfertility (8-48%) among obese men. Low genetically predicted BMI values were also related to greater subfertility risk in men at the lower end of the BMI distribution. A genetically predicted BMI of 23 and 25 kg/m2 was linked to the lowest subfertility risk in women and men, respectively. LIMITATIONS, REASONS FOR CAUTION: The main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values <20.0 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: Our results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values <20 kg/m2 may have an increased risk of subfertility. These results suggest that BMI values between 20 and 25 kg/m2 are optimal for a minimal risk of subfertility. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

13.
PLoS Med ; 18(9): e1003757, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34525088

RESUMO

BACKGROUND: Spending more time active (and less sedentary) is associated with health benefits such as improved cardiovascular health and lower risk of all-cause mortality. It is unclear whether these associations differ depending on whether time spent sedentary or in moderate-vigorous physical activity (MVPA) is accumulated in long or short bouts. In this study, we used a novel method that accounts for substitution (i.e., more time in MVPA means less time sleeping, in light activity or sedentary) to examine whether length of sedentary and MVPA bouts associates with all-cause mortality. METHODS AND FINDINGS: We used data on 79,503 adult participants from the population-based UK Biobank cohort, which recruited participants between 2006 and 2010 (mean age at accelerometer wear 62.1 years [SD = 7.9], 54.5% women; mean length of follow-up 5.1 years [SD = 0.73]). We derived (1) the total time participants spent in activity categories-sleep, sedentary, light activity, and MVPA-on average per day; (2) time spent in sedentary bouts of short (1 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration; and (3) MVPA bouts of very short (1 to 9 minutes), short (10 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration. We used Cox proportion hazards regression to estimate the association of spending 10 minutes more average daily time in one activity or bout length category, coupled with 10 minutes less time in another, with all-cause mortality. Those spending more time in MVPA had lower mortality risk, irrespective of whether this replaced time spent sleeping, sedentary, or in light activity, and these associations were of similar magnitude (e.g., hazard ratio [HR] 0.96 [95% CI: 0.94, 0.97; P < 0.001] per 10 minutes more MVPA, coupled with 10 minutes less light activity per day). Those spending more time sedentary had higher mortality risk if this replaced light activity (HR 1.02 [95% CI: 1.01, 1.02; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less light activity per day) and an even higher risk if this replaced MVPA (HR 1.06 [95% CI: 1.05, 1.08; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less MVPA per day). We found little evidence that mortality risk differed depending on the length of sedentary or MVPA bouts. Key limitations of our study are potential residual confounding, the limited length of follow-up, and use of a select sample of the United Kingdom population. CONCLUSIONS: We have shown that time spent in MVPA was associated with lower mortality, irrespective of whether it replaced time spent sleeping, sedentary, or in light activity. Time spent sedentary was associated with higher mortality risk, particularly if it replaced MVPA. This emphasises the specific importance of MVPA. Our findings suggest that the impact of MVPA does not differ depending on whether it is obtained from several short bouts or fewer longer bouts, supporting the recent removal of the requirement that MVPA should be accumulated in bouts of 10 minutes or more from the UK and the United States policy. Further studies are needed to investigate causality and explore health outcomes beyond mortality.


Assuntos
Exercício Físico , Estilo de Vida Saudável , Comportamento de Redução do Risco , Comportamento Sedentário , Ciclos de Atividade , Adulto , Idoso , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esforço Físico , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Fatores de Risco , Sono , Fatores de Tempo , Reino Unido
14.
Diabetologia ; 64(12): 2790-2802, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34542646

RESUMO

AIMS/HYPOTHESIS: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal 'metabolically favourable adiposity' on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI). METHODS: To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers. RESULTS: Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (-94 [95% CI -150, -38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m2] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it. CONCLUSIONS/INTERPRETATION: Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile. DATA AVAILABILITY: The data for the genome-wide association studies (GWAS) of BMI are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files . The data for the GWAS of body fat percentage are available at https://walker05.u.hpc.mssm.edu .

15.
Nat Commun ; 12(1): 5640, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561430

RESUMO

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Doença das Coronárias/prevenção & controle , Amidas/uso terapêutico , Benzodiazepinas/uso terapêutico , Doenças Cardiovasculares/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/metabolismo , Ésteres/uso terapêutico , Humanos , Análise da Randomização Mendeliana , Oxazolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Compostos de Sulfidrila/uso terapêutico
16.
PLoS Genet ; 17(8): e1009703, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34370750

RESUMO

Over the last decade the availability of SNP-trait associations from genome-wide association studies has led to an array of methods for performing Mendelian randomization studies using only summary statistics. A common feature of these methods, besides their intuitive simplicity, is the ability to combine data from several sources, incorporate multiple variants and account for biases due to weak instruments and pleiotropy. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well developed summary data methods to individual level data, and to explore the use of more sophisticated causal methods allowing for non-linearity and effect modification. In this paper we describe a general procedure for optimally applying any two sample summary data method using one sample data. Our procedure first performs a meta-analysis of summary data estimates that are intentionally contaminated by collider bias between the genetic instruments and unmeasured confounders, due to conditioning on the observed exposure. These estimates are then used to correct the standard observational association between an exposure and outcome. Simulations are conducted to demonstrate the method's performance against naive applications of two sample summary data MR. We apply the approach to the UK Biobank cohort to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes. Our approach can be viewed as a generalization of Dudbridge et al. (Nat. Comm. 10: 1561), who developed a technique to adjust for index event bias when uncovering genetic predictors of disease progression based on case-only data. Our work serves to clarify that in any one sample MR analysis, it can be advantageous to estimate causal relationships by artificially inducing and then correcting for collider bias.


Assuntos
Biologia Computacional/métodos , Hemoglobina A Glicada/metabolismo , Análise da Randomização Mendeliana/métodos , Transtornos do Sono-Vigília/genética , Algoritmos , Bancos de Espécimes Biológicos , Bases de Dados Genéticas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Reino Unido
17.
Metabolites ; 11(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34436471

RESUMO

Many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or have an offspring born small/large for gestational age (SGA/LGA) do not meet the criteria for high-risk pregnancies based upon certain maternal risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders. These have largely been based on targeted platforms or focused on a single pregnancy outcome. The aim of this study was to assess the predictive ability of an untargeted platform of over 700 metabolites to predict the above pregnancy-related disorders in two cohorts. We used data collected from women in the Born in Bradford study (BiB; two sub-samples, n = 2000 and n = 1000) and the Pregnancy Outcome Prediction study (POPs; n = 827) to train, test and validate prediction models for GDM, PE, GHT, SGA, LGA and sPTB. We compared the predictive performance of three models: (1) risk factors (maternal age, pregnancy smoking, BMI, ethnicity and parity) (2) mass spectrometry (MS)-derived metabolites (n = 718 quantified metabolites, collected at 26-28 weeks' gestation) and (3) combined risk factors and metabolites. We used BiB for the training and testing of the models and POPs for independent validation. In both cohorts, discrimination for GDM, PE, LGA and SGA improved with the addition of metabolites to the risk factor model. The models' area under the curve (AUC) were similar for both cohorts, with good discrimination for GDM (AUC (95% CI) BiB 0.76 (0.71, 0.81) and POPs 0.76 (0.72, 0.81)) and LGA (BiB 0.86 (0.80, 0.91) and POPs 0.76 (0.60, 0.92)). Discrimination was improved for the combined models (compared to the risk factors models) for PE and SGA, with modest discrimination in both studies (PE-BiB 0.68 (0.58, 0.78) and POPs 0.66 (0.60, 0.71); SGA-BiB 0.68 (0.63, 0.74) and POPs 0.64 (0.59, 0.69)). Prediction for sPTB was poor in BiB and POPs for all models. In BiB, calibration for the combined models was good for GDM, LGA and SGA. Retained predictors include 4-hydroxyglutamate for GDM, LGA and PE and glycerol for GDM and PE. MS-derived metabolomics combined with maternal risk factors improves the prediction of GDM, PE, LGA and SGA, with good discrimination for GDM and LGA. Validation across two very different cohorts supports further investigation on whether the metabolites reflect novel causal paths to GDM and LGA.

18.
Am J Epidemiol ; 190(12): 2680-2689, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215868

RESUMO

Longitudinal data are necessary to reveal changes within an individual as he or she ages. However, rarely will a single cohort study capture data throughout a person's entire life span. Here we describe in detail the steps needed to develop life-course trajectories from cohort studies that cover different and overlapping periods of life. Such independent studies are probably from heterogenous populations, which raises several challenges, including: 1) data harmonization (deriving new harmonized variables from differently measured variables by identifying common elements across all studies); 2) systematically missing data (variables not measured are missing for all participants in a cohort); and 3) model selection with differing age ranges and measurement schedules. We illustrate how to overcome these challenges using an example which examines the associations of parental education, sex, and race/ethnicity with children's weight trajectories. Data were obtained from 5 prospective cohort studies (carried out in Belarus and 4 regions of the United Kingdom) spanning data collected from birth to early adulthood during differing calendar periods (1936-1964, 1972-1979, 1990-2012, 1996-2016, and 2007-2015). Key strengths of our approach include modeling of trajectories over wide age ranges, sharing of information across studies, and direct comparison of the same parts of the life course in different geographical regions and time periods. We also introduce a novel approach of imputing individual-level covariates of a multilevel model with a nonlinear growth trajectory and interactions.

20.
Hum Reprod ; 36(8): 2403-2413, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34136910

RESUMO

STUDY QUESTION: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction? SUMMARY ANSWER: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation. WHAT IS KNOWN ALREADY: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes. STUDY DESIGN, SIZE, DURATION: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls). MAIN RESULTS AND THE ROLE OF CHANCE: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling. LIMITATIONS, REASONS FOR CAUTIONS: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction. WIDER IMPLICATIONS OF THE FINDINGS: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health. STUDY FUNDING/COMPETING INTERESTS(S): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Metilação de DNA , Infecções por HIV , Adulto , Austrália , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Sangue Fetal , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Reprodução
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