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1.
J Natl Cancer Inst ; 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34743211

RESUMO

The burden of cancer from a clinical, societal, and economic viewpoint continues to increase in all parts of the world, along with much debate regarding how to confront this. Projected increases in cancer indicate a 50% increase in the numbers of cases over the next two decades, with the greatest proportional increase in low- and medium-income settings. In contrast to the historic high cancer burden due to viral and bacterial infections in these regions, future increases are expected to be due to cancers linked to 'westernization' including breast, colorectum, lung, and prostate cancer. Identifying the reasons underlying these increases will be paramount to informing prevention efforts. Evidence from epidemiological and laboratory studies conducted in high income countries over the last 70 years have led to the conclusion that about 40% of the cancer burden is explained by known risk factors, the two most important being tobacco and obesity in that order, raising the question of what is driving the rest of the cancer burden. International cancer statistics continue to show that about 80% of the cancer burden in high income countries could be preventable in principle, implying that there are important environmental or lifestyle risk factors for cancer that have not yet been discovered. Emerging genomic evidence from population and experimental studies points to an important role for non-mutagenic promoters in driving cancer incidence rates. New research strategies and infrastructures that combine population-based and laboratory research at a global level are required to break this deadlock.

2.
Lancet Healthy Longev ; 2(6): e317-e326, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34729547

RESUMO

Background: Apolipoprotein B (apoB) is emerging as the crucial lipoprotein trait for the role of lipoprotein lipids in the aetiology of coronary heart disease. In this study, we evaluated the effects of genetically predicted apoB on outcomes in first-degree relatives. Methods: Data on lipoprotein lipids and disease outcomes in first-degree relatives were obtained from the UK Biobank study. We did a univariable mendelian randomisation analysis using a weighted genetic instrument for apoB. For outcomes with which apoB was associated at a false discovery rate (FDR) of less than 5%, multivariable mendelian randomisation analyses were done, including genetic instruments for LDL cholesterol and triglycerides. Associations between apoB and self-reported outcomes in first-degree relatives were characterised for 12 diseases (including heart disease, stroke, and hypertension) and parental vital status together with age at death. Estimates were inferred causal effects per 1 SD elevated lipoprotein trait (for apoB, 1 SD=0·24 g/L). Replication of estimates for lifespan and type 2 diabetes was done using conventional two-sample mendelian randomisation with summary estimates from genome-wide association study consortia. Findings: In univariable mendelian randomisation, genetically elevated apoB in participants was identified to lead to a shorter lifespan in parents (fathers: 0·89 years of life lost per 1 SD higher apoB in offspring, 95% CI 0·63-1·16, FDR-adjusted p=4·0 × 10-10; mothers: 0·48 years of life lost per 1 SD higher apoB in offspring, 0·25-0·71, FDR-adjusted p=1·7 × 10-4). The effects were strengthened to around 2 years of life lost in multivariable mendelian randomisation and were replicated in conventional two-sample mendelian randomisation (odds ratio [OR] of surviving to the 90th centile of lifespan: 0·38 per 1 SD higher apoB in offspring, 95% CI 0·22-0·65). Genetically elevated apoB caused higher risks of heart disease in all first-degree relatives and a higher risk of stroke in mothers. Findings in first-degree relatives were replicated in two-sample multivariable mendelian randomisation, which identified apoB to increase (OR 2·32 per 1 SD higher apoB, 95% CI 1·49-3·61) and LDL cholesterol to decrease (0·34 per 1 SD higher LDL cholesterol, 0·21-0·54) the risk of type 2 diabetes. Interpretation: Higher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes. Funding: British Heart Foundation, UK Medical Research Council, and UK Research and Innovation.

3.
Lancet ; 398(10313): 1803-1810, 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34774144

RESUMO

BACKGROUND: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials. METHODS: We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons. FINDINGS: 145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84-0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76-0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76-0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of ß blockers (RR 1·48 [1·27-1·72]) and thiazide diuretics (RR 1·20 [1·07-1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92-1·13]). INTERPRETATION: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes. FUNDING: British Heart Foundation, National Institute for Health Research, and Oxford Martin School.

4.
Psychoneuroendocrinology ; 135: 105577, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34823140

RESUMO

INTRODUCTION: Associations between measures of socio-economic position and cortisol remain controversial. We examined the association between social class and cortisol reactivity in an aging male population. METHODS: The Speedwell cohort study recruited 2348 men aged 45-59 years from primary care between 1979 and 1982 (phase I) where occupational social class was used to classify socioeconomic position. Men were seen on four more occasions, the last being between 1997 and 1999 (phase 5) when salivary samples were obtained capturing cortisol reactivity to stressors (cognitive test and venepuncture) and circadian variations (awakening and night-time cortisol levels, circadian slope and area under curve) at morning and afternoon clinic sessions. Longitudinal association between social class at phase 3 and log-transformed salivary cortisol measures at phase 5 was assessed using multivariable linear regression adjusted for variables associated with sampling time and age as a potential confounder, stratified by time of clinic session. We also explored possible mediation by psychosocial factors (e.g. work dislike) and health-related factors (e.g. waist-to-hip ratio and high-density lipoprotein cholesterol). RESULTS: From 1768 living men, 1003 men (57%) attended a clinic at phase five, 854 participants (85% of attendees) returned home cortisol samples (mean age 71.7 years). We found little evidence of association between social class and baseline cortisol (i.e. prior to stress), cortisol response to stressors, and cortisol diurnal variation. However, we found lower social class was associated with higher and delayed post-stress recovery cortisol for participants that visited the clinic in the morning (adjusted ß coefficient for manual versus non-manual 0.25 ng/ml; 95% CI: 0.06-0.48; P = 0.008). This association did not appear to be mediated by any of the measured psychosocial or health-related factors. CONCLUSION: Our data did not show an overall association between social class and cortisol variability either diurnal or in response to a stressor. Lower social class was associated with a slower time to recover from exposure to stress in the morning, thereby increasing overall cortisol exposure. These findings provide some evidence for a mechanism that may contribute to the association between lower social class and a higher risk of adverse health outcomes.

6.
Sci Rep ; 11(1): 22408, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789785

RESUMO

Childhood BMI shows associations with adult mortality, but these may be influenced by effects of ill health in childhood on BMI and later mortality. To avoid this, we used offspring childhood BMI as an instrumental variable (IV) for own BMI in relation to mortality and compared it with conventional associations of own childhood BMI and own mortality. We included 36,097 parent-offspring pairs with measured heights and weights from the Copenhagen School Health Records Register and register-based information on death. Hazard ratios (HR) were estimated using adjusted Cox regression models. For all-cause mortality, per zBMI at age 7 the conventional HR = 1.07 (95%CI: 1.04-1.09) in women and 1.02 (95%CI: 0.92-1.14) in men, whereas the IV HR = 1.23 (95%CI: 1.15-1.32) in women and 1.05 (95%CI: 0.94-1.17) in men. Per zBMI at age 13, the conventional HR = 1.11 (95%CI: 1.08-1.15) in women and 1.03 (95%CI: 0.99-1.06) in men, whereas the IV HR = 1.30 (95%CI: 1.19-1.42) in women and 1.15 (95%CI: 1.04-1.29) in men. Only conventional models showed indications of J-shaped associations. Our IV analyses suggest that there is a causal relationship between BMI and mortality that is positive at both high and low BMI values.

7.
PLoS Genet ; 17(11): e1009883, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34735433

RESUMO

Spousal comparisons have been proposed as a design that can both reduce confounding and estimate effects of the shared adulthood environment. However, assortative mating, the process by which individuals select phenotypically (dis)similar mates, could distort associations when comparing spouses. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological research such as genetic association studies. We demonstrated that the WSP model can reduce confounding but may be susceptible to collider bias arising from conditioning on assorted spouse pairs. Analyses using UK Biobank spouse pairs found that WSP genetic association estimates were smaller than estimates from random pairs for height, educational attainment, and BMI variants. Within-sibling pair estimates, robust to demographic and parental effects, were also smaller than random pair estimates for height and educational attainment, but not for BMI. WSP models, like other within-family models, may reduce confounding from demographic factors in genetic association estimates, and so could be useful for triangulating evidence across study designs to assess the robustness of findings. However, WSP estimates should be interpreted with caution due to potential collider bias.

8.
J Affect Disord ; 295: 974-980, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706471

RESUMO

BACKGROUND: Previous research on the relationship between children's depressive and externalising symptoms, experience of school, and academic attainment is inconclusive. The aims of this study were (i) to test bidirectional associations between children's school experience and depressive and externalising symptoms at age 10-11 and 13-14, (ii) to ascertain whether school experience age 13-14 is associated with academic attainment age 16, and (iii) to test whether school experience mediates the relationship between depressive or externalising symptoms and attainment. METHODS: Data was used from the Avon Longitudinal Study of Parents and Children (n=6,409). A cross-lagged model was used to investigate bidirectional associations between school experience (enjoyment and connectedness) and depression and externalising at age 10-11 and 13-14. The same framework was used to test if school experience aged 13-14 mediated associations of depressive and externalising symptoms with later attainment. RESULTS: Depressive and externalising symptoms at 10-11 were negatively associated with school connectedness (depressive: standardised ß=-0.06, CI: -0.11, 0.01; externalizing: ß=-0.13, CI: -0.17, -0.08), and school enjoyment at 13-14 (depressive ß=-0.04, -0.08, 0.03; externalising: ß=-0.08, CI: -0.13, -0.03). School enjoyment at 13-14 was positively associated with attainment at 16 (ß=0.10, CI: 0.04, 0.15), and partially mediated associations between depressive and externalising symptoms at 10-11 and attainment at 16 (depressive: proportion mediated 2.2%, CI: -1.5, 5.9; externalising: proportion mediated; 4.7%, CI: 0.7, 10.1,). LIMITATIONS: Results may be subject to residual confounding. CONCLUSIONS: School enjoyment is a potentially modifiable risk factor that may affect educational attainment of adolescents with depressive or externalising symptoms.


Assuntos
Prazer , Instituições Acadêmicas , Adolescente , Criança , Depressão/epidemiologia , Humanos , Estudos Longitudinais , Estudos Prospectivos , Reino Unido/epidemiologia
9.
Hum Mol Genet ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542150

RESUMO

BACKGROUND: The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels. METHODS: Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. RESULTS: Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained > 9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF-23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes, followed by targeted MR suggested causal effects of liability of Crohn's disease risk [IVW beta = 0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho. CONCLUSIONS: Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively.

10.
Bone ; 153: 116146, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34389476

RESUMO

OBJECTIVE: It remains unclear how the different features of radiographic hip osteoarthritis (rHOA) contribute to hip pain. We examined the relationship between rHOA, including its individual components, and hip pain using a novel dual-energy x-ray absorptiometry (DXA)-based method. METHODS: Hip DXAs were obtained from UK Biobank. A novel automated method obtained minimum joint space width (mJSW) from points placed around the femoral head and acetabulum. Osteophyte areas at the lateral acetabulum, superior and inferior femoral head were derived manually. Semi-quantitative measures of osteophytes and joint space narrowing (JSN) were combined to define rHOA. Logistic regression was used to examine the relationships between these variables and hip pain, obtained via questionnaires. RESULTS: 6807 hip DXAs were examined. rHOA was present in 353 (5.2%) individuals and was associated with hip pain [OR 2.42 (1.78-3.29)] and hospital diagnosed OA [6.01 (2.98-12.16)]. Total osteophyte area but not mJSW was associated with hip pain in mutually adjusted models [1.31 (1.23-1.39), 0.95 (0.87-1.04) respectively]. On the other hand, JSN as a categorical variable showed weak associations between grade ≥ 1 and grade ≥ 2 JSN with hip pain [1.30 (1.06-1.60), 1.80 (1.34-2.42) respectively]. Acetabular, superior and inferior femoral osteophyte areas were all independently associated with hip pain [1.13 (1.06-1.20), 1.13 (1.05-1.24), 1.10 (1.03-1.17) respectively]. CONCLUSION: In this cohort, the relationship between rHOA and prevalent hip pain was explained by 2-dimensional osteophyte area, but not by the apparent mJSW. Osteophytes at different locations showed important, potentially independent, associations with hip pain, possibly reflecting the contribution of distinct biomechanical pathways.


Assuntos
Osteoartrite do Quadril , Osteófito , Absorciometria de Fóton , Bancos de Espécimes Biológicos , Estudos Transversais , Humanos , Osteoartrite do Quadril/diagnóstico por imagem , Osteófito/diagnóstico por imagem , Dor , Radiografia , Reino Unido/epidemiologia
11.
J Parkinsons Dis ; 11(4): 1981-1993, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34275906

RESUMO

BACKGROUND: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. OBJECTIVE: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. METHODS: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. RESULTS: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921-0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025-1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979-0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. CONCLUSION: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

12.
BMC Pulm Med ; 21(1): 246, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294062

RESUMO

BACKGROUND: Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR). METHODS: Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates. RESULTS: We found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak. CONCLUSION: We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.


Assuntos
Cognição/fisiologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/psicologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fatores de Risco
14.
Hum Mol Genet ; 30(21): 2027-2039, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33961016

RESUMO

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

16.
Am J Psychiatry ; 178(8): 752-760, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33900814

RESUMO

OBJECTIVE: Autism spectrum disorder (ASD) is currently considered an early-onset neurodevelopmental condition. Follow-up studies of clinic-ascertained autism suggest that autistic symptoms typically decline with age, although symptom improvement is limited for some. To date there have been no population-based prospective studies investigating the natural history of autistic symptoms from childhood to adulthood. The aim of this study was to characterize the development and heterogeneity of autistic symptoms in a population-based cohort from childhood to age 25. METHODS: Data were analyzed in a prospective U.K. population-based cohort (ALSPAC). Trajectories were derived using five assessments of the parent-rated Social and Communication Disorders Checklist (SCDC) spanning ages 7-25. Additional measures were used to validate symptom trajectories. RESULTS: Three distinct SCDC symptom trajectory classes were identified: low (88.5%), declining (5.0%), and late-emerging (6.5%). Both the declining and late-emerging trajectory classes were associated with child and adult ASD measures, low IQ, communication problems, peer problems, and worse adult functioning compared with the low trajectory class. Male sex was associated with a higher likelihood of being in the declining trajectory class (odds ratio=2.84, 95% CI=2.19, 3.69). This sex difference was not observed in the late-emerging class (odds ratio=1.00, 95% CI=0.80, 1.24) compared with the low trajectory class. CONCLUSIONS: ASD symptom levels that emerged early tended to decline across development, although impairment was still present in adulthood for some. For others, autistic symptoms emerged across adolescence and adulthood. This challenges our current understanding that ASD symptoms inevitably first manifest early in development.


Assuntos
Transtorno do Espectro Autista/patologia , Atividades Cotidianas/psicologia , Adolescente , Adulto , Idade de Início , Transtorno do Espectro Autista/psicologia , Lista de Checagem , Criança , Comunicação , Progressão da Doença , Feminino , Humanos , Inteligência , Estudos Longitudinais , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Reino Unido , Adulto Jovem
17.
Genome Med ; 13(1): 38, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663581

RESUMO

BACKGROUND: Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. METHODS: First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. RESULTS: The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. CONCLUSIONS: The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.

18.
Sci Adv ; 7(11)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33692100

RESUMO

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

19.
Int J Epidemiol ; 50(4): 1229-1240, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-33712841

RESUMO

BACKGROUND: Shift work is associated with increased cardiometabolic disease risk. This observation may be partly explained by cardiometabolic risk factors having a role in the selection of individuals into or out of shift work. We performed Mendelian randomization (MR) analyses in the UK Biobank (UKB) to test this hypothesis. METHODS: We used genetic risk scores (GRS) to proxy nine cardiometabolic risk factors and diseases (including educational attainment, body mass index (BMI), smoking, and alcohol consumption), and tested associations of each GRS with self-reported frequency of current shift work among employed UKB participants of European ancestry (n = 190 573). We used summary-level MR sensitivity analyses to assess robustness of the identified effects, and we tested whether effects were mediated through sleep timing preference. RESULTS: Genetically instrumented liability to lower educational attainment (odds ratio (OR) per 3.6 fewer years in educational attainment = 2.40, 95% confidence interval (CI) = 2.22-2.59, P = 4.84 × 10-20) and higher body mass index (OR per 4.7 kg/m2 higher BMI = 1.30, 95% CI = 1.14-1.47, P = 5.85 × 10-5) increased odds of reporting participation in frequent shift work. Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy. No selection effects were evident for the remaining exposures, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate the effects of BMI and educational attainment on selection into shift work. CONCLUSIONS: Liability to lower educational attainment and higher BMI may influence selection into shift work. This phenomenon may bias epidemiological studies of shift work that are performed in the UKB.


Assuntos
Análise da Randomização Mendeliana , Jornada de Trabalho em Turnos , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Reino Unido/epidemiologia
20.
PLoS Med ; 18(2): e1003536, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33630834

RESUMO

BACKGROUND: Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). METHODS AND FINDINGS: For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. CONCLUSIONS: Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Análise da Randomização Mendeliana , Deficiência de Vitamina D/genética , Vitamina D/sangue , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 2/complicações , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Deficiência de Vitamina D/sangue
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