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2.
Brain ; 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36310536

RESUMO

Higher educational attainment (EA) is observationally associated with lower risk of Alzheimer's disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer's disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between EA, structural brain reserve as proxied by MRI phenotypes, and Alzheimer's disease. Summary statistics were obtained from genome-wide association studies of EA (n = 1,131,881), late-onset Alzheimer's disease (35,274 cases, 59,163 controls), and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33,211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) EA and Alzheimer's disease, (ii) EA and imaging-derived phenotypes, (iii) imaging-derived phenotypes and Alzheimer's disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer's disease risk. Genetically-proxied EA was inversely associated with Alzheimer's disease (odds ratio per standard deviation [SD] increase in genetically-predicted years of schooling (YOS) = 0.70, 95% confidence interval [CI] 0.60, 0.80). There were positive associations between genetically-predicted EA and four cortical metrics (SD units change in imaging phenotype per one SD increase in genetically-predicted YOS: surface area 0.30 [95% CI 0.20, 0.40]; volume 0.29 [95% CI 0.20, 0.37]; intrinsic curvature 0.18 [95% CI 0.11, 0.25]; local gyrification index 0.21 [95% CI 0.11, 0.31]), and inverse associations with cortical intracellular volume fraction (-0.09 [95% CI -0.15, -0.03]) and white matter hyperintensities volume (-0.14 [95% CI -0.23, -0.05]). Genetically-proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with EA (SD units change in YOS per one SD increase in respective genetically-predicted imaging phenotype: 0.13 [95% CI 0.10, 0.16]; 0.15 [95% CI 0.11, 0.19]; 0.12 [95% CI 0.04, 0.19]). We found no evidence of associations between genetically-predicted imaging-derived phenotypes and Alzheimer's disease. The inverse association of genetically-predicted EA with Alzheimer's disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer's disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer's disease. The protective effect of education on Alzheimer's disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.

3.
Circulation ; 146(20): 1507-1517, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36314129

RESUMO

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.


Assuntos
Doenças Cardiovasculares , Doença das Coronárias , Diabetes Mellitus , Acidente Vascular Cerebral , Humanos , Análise da Randomização Mendeliana/métodos , Estudos Prospectivos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Fatores de Risco , Diabetes Mellitus/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Rim
4.
Genet Epidemiol ; 2022 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-36273411

RESUMO

Mendelian randomization (MR) is the use of genetic variants to assess the existence of a causal relationship between a risk factor and an outcome of interest. Here, we focus on two-sample summary-data MR analyses with many correlated variants from a single gene region, particularly on cis-MR studies which use protein expression as a risk factor. Such studies must rely on a small, curated set of variants from the studied region; using all variants in the region requires inverting an ill-conditioned genetic correlation matrix and results in numerically unstable causal effect estimates. We review methods for variable selection and estimation in cis-MR with summary-level data, ranging from stepwise pruning and conditional analysis to principal components analysis, factor analysis, and Bayesian variable selection. In a simulation study, we show that the various methods have comparable performance in analyses with large sample sizes and strong genetic instruments. However, when weak instrument bias is suspected, factor analysis and Bayesian variable selection produce more reliable inferences than simple pruning approaches, which are often used in practice. We conclude by examining two case studies, assessing the effects of low-density lipoprotein-cholesterol and serum testosterone on coronary heart disease risk using variants in the HMGCR and SHBG gene regions, respectively.

5.
Nat Commun ; 13(1): 6143, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253349

RESUMO

Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.


Assuntos
Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Acidente Vascular Cerebral , Fibrilação Atrial/genética , Proteínas Sanguíneas/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Proteoma/genética , Fatores de Risco , Acidente Vascular Cerebral/genética
6.
Neurol Genet ; 8(5): e200014, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36046424

RESUMO

Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits. Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.

7.
Int J Cancer ; 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36093575

RESUMO

Morning chronotype has been associated with a reduced risk of prostate and breast cancer. However, few studies have examined whether chronotype is associated with digestive tract cancer risk. We conducted a Mendelian randomization (MR) study to assess the associations of chronotype with major digestive tract cancers. A total of 317 independent genetic variants associated with chronotype at the genome-wide significance level (P < 5 × 10-8 ) were used as instrumental variables from a genome-wide meta-analysis of 449 734 individuals. Summary-level data on overall and six digestive tract cancers, including esophageal, stomach, liver, biliary tract, pancreatic and colorectal cancers, were obtained from the UK Biobank (11 952 cases) and FinnGen (7638 cases) study. Genetic liability to morning chronotype was associated with reduced risk of overall digestive tract cancer and cancers of stomach, biliary tract and colorectum in UK Biobank. The associations for the overall digestive tract, stomach and colorectal cancers were directionally replicated in FinnGen. In the meta-analysis of the two sources, genetic liability to morning chronotype was associated with a decreased risk of overall digestive tract cancer (odds ratio [OR] 0.94, 95% confidence interval [CI]: 0.90-0.98), stomach cancer (OR 0.84, 95% CI: 0.73-0.97) and colorectal cancer (OR 0.92, 95% CI: 0.87-0.98), but not with the other studied cancers. The associations were consistent in multivariable MR analysis with adjustment for genetically predicted sleep duration, short sleep, insomnia and body mass index. The study provided MR evidence of inverse associations of morning chronotype with digestive tract cancer, particularly stomach and colorectal cancers.

8.
Clin Nutr ; 41(10): 2113-2123, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36067583

RESUMO

BACKGROUND: Coffee contains many bioactive chemicals and associations with cancer have been reported in observational studies. In this Mendelian randomisation (MR) study we investigated the causal associations of coffee consumption with a broad range of cancers. MATERIALS AND METHODS: Twelve independent genetic variants proxied coffee consumption. Genetically-predicted risk of any cancer (59,647 cases) and 22 site-specific cancers was estimated in European-descent individuals in UK Biobank. Univariable and multivariable MR analyses were conducted. RESULTS: Genetically-predicted coffee consumption was not associated with risk of any cancer in the main analysis (OR 1.05, 95% CI 0.98-1.14, p = 0.183) but was associated with an increased risk of digestive system cancer (OR 1.28, 95% CI 1.09-1.51, p = 0.003), driven by a strong association with oesophageal cancer (OR 2.79, 95% CI 1.73-4.50, p = 2.5×10-5). This association was consistent after adjustment for genetically-predicted body mass index, smoking and alcohol consumption. There was no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied. However, genetically-predicted coffee consumption was associated with increased risk of multiple myeloma (OR 2.25, 95% CI 1.30-3.89, p = 0.004) and reduced ovarian cancer risk (OR 0.63, 95% CI 0.43-0.93, p = 0.020). CONCLUSIONS: This MR study provides strong support for a causal association of coffee consumption with oesophageal cancer, but not for the majority of cancer types, and the underlying mechanisms require investigation.


Assuntos
Neoplasias Esofágicas , Neoplasias Ovarianas , Café/efeitos adversos , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/genética , Feminino , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
PLoS One ; 17(8): e0272807, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35984822

RESUMO

INTRODUCTION: In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. RESULTS: Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780). CONCLUSIONS: This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.


Assuntos
Embolia Pulmonar , Tromboembolia Venosa , Humanos , Hidrocortisona , Análise da Randomização Mendeliana , Embolia Pulmonar/complicações , Fatores de Risco , Tromboembolia Venosa/complicações , Tromboembolia Venosa/genética
10.
Clin Nutr ; 41(9): 2031-2035, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35986965

RESUMO

BACKGROUND & AIMS: Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers. METHODS: Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrumental variables. Effect size estimates for the genetic associations of the vitamin C-associated genetic variants with six major malignancies of digestive system were obtained from the FinnGen (N = 309 154) and UK Biobank (N = 367 542) studies. Results from the two studies were combined using meta-analysis. RESULTS: Genetically predicted higher circulating vitamin C showed a suggestive association with lower risk of small intestine and colorectal cancer after accounting for multiple testing. The odds ratio per 1 standard deviation increment in circulating vitamin C was 0.55 (95% confidence interval 0.32-0.94; P = 0.029) for small intestine cancer and 0.84 (95% confidence interval 0.73-0.96; P = 0.013) for colorectal cancer. There was a suggestive association between genetically predicted higher circulating vitamin C with lower risk of liver cancer in FinnGen but no association in the meta-analysis (odds ratio 0.69; 95% CI 0.36-1.32; P = 0.265). Genetically predicted circulating vitamin C was not associated with cancers of the esophagus, stomach, or pancreas. CONCLUSION: This Mendelian randomization study indicates that vitamin C might play a role in the prevention of small intestine and colorectal cancer.


Assuntos
Neoplasias Colorretais , Neoplasias do Sistema Digestório , Ácido Ascórbico , Neoplasias do Sistema Digestório/epidemiologia , Neoplasias do Sistema Digestório/genética , Humanos , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Vitaminas
11.
PLoS Comput Biol ; 18(8): e1010268, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36037248

RESUMO

Bias from weak instruments may undermine the ability to estimate causal effects in instrumental variable regression (IVR). We present here a new approach to handling weak instrument bias through the application of a new type of instrumental variable coined 'Cross-Fitted Instrument' (CFI). CFI splits the data at random and estimates the impact of the instrument on the exposure in each partition. These estimates are then used to perform an IVR on each partition. We adapt CFI to the Mendelian randomization (MR) setting and term this adaptation 'Cross-Fitting for Mendelian Randomization' (CFMR). We show that, even when using weak instruments, CFMR is, at worst, biased towards the null, which makes it a conservative one-sample MR approach. In particular, CFMR remains conservative even when the two samples used to perform the MR analysis completely overlap, whereas current state-of-the-art approaches (e.g., MR RAPS) display substantial bias in this setting. Another major advantage of CFMR lies in its use of all of the available data to select genetic instruments, which maximizes statistical power, as opposed to traditional two-sample MR where only part of the data is used to select the instrument. Consequently, CFMR is able to enhance statistical power in consortia-led meta-analyses by enabling a conservative one-sample MR to be performed in each cohort prior to a meta-analysis of the results across all the cohorts. In addition, CFMR enables a cross-ethnic MR analysis by accounting for ethnic heterogeneity, which is particularly important in meta-analyses where the participating cohorts may have different ethnicities. To our knowledge, none of the current MR approaches can account for such heterogeneity. Finally, CFMR enables the application of MR to exposures that are either rare or difficult to measure, which would normally preclude their analysis in the regular two-sample MR setting.


Assuntos
Análise da Randomização Mendeliana , Viés , Causalidade , Humanos , Análise da Randomização Mendeliana/métodos
12.
Circ Res ; 131(6): 545-554, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35946401

RESUMO

BACKGROUND: Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. METHODS: Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). RESULTS: In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03-1.76]; P=0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08-1.48]; P=0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00-1.35]; P=0.049). CONCLUSIONS: Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.


Assuntos
Diabetes Mellitus Tipo 2 , Rigidez Vascular , Bancos de Espécimes Biológicos , Artéria Braquial , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Glucose , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Análise de Onda de Pulso , Rigidez Vascular/genética
13.
BMC Med ; 20(1): 272, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36045366

RESUMO

BACKGROUND: L-carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of L-carnitine, we assessed how genetically different levels of L-carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and L-carnitine in men, we also examined sex-specific associations. METHODS: We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict L-carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with L-carnitine) and combined them using inverse variance weighting. In sensitivity analysis, we used different analysis methods robust to pleiotropy and replicated using an L-carnitine isoform, acetyl-carnitine. RESULTS: Genetically predicted L-carnitine was nominally associated with higher risk of CAD overall (OR 1.07 per standard deviation (SD) increase in L-carnitine, 95% CI 1.02 to 1.11) and in men (OR 1.09, 95% CI 1.02 to 1.16) but had a null association in women (OR 1.00, 95% CI 0.92 to 1.09). These associations were also robust to different methods and evident for acetyl-carnitine. CONCLUSIONS: Our findings do not support a beneficial association of L-carnitine with CVD and its risk factors but suggest potential harm. L-carnitine may also exert a sex-specific role in CAD. Consideration of the possible sex disparity and exploration of the underlying pathways would be worthwhile.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Carnitina , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
BMC Med ; 20(1): 245, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35948913

RESUMO

BACKGROUND: Interleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors. METHODS: Among 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors. RESULTS: The study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06-1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL. CONCLUSIONS: Any benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.


Assuntos
Proteína C-Reativa , Doenças Cardiovasculares , Biomarcadores , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , LDL-Colesterol , Feminino , Humanos , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco
16.
EBioMedicine ; 82: 104154, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35816897

RESUMO

BACKGROUND: The causal association between cigarette smoking and several diseases remains equivocal. The purpose of this study was to appraise the causal role of smoking in a wide range of diseases by summarizing the evidence from Mendelian randomization (MR) studies. METHODS: MR studies on genetic liability to smoking initiation or lifetime smoking (composite of smoking initiation, heaviness, duration, and cessation) in relation to circulatory system, digestive system, nervous system, musculoskeletal system, endocrine, metabolic, and eye diseases, and neoplasms published until February 15, 2022, were identified in PubMed. De novo MR analyses were performed using summary statistics data from genome-wide association studies. Meta-analysis was applied to combine study-specific estimates. FINDINGS: Meta-analyses of findings of 29 published MR studies and 123 de novo MR analyses of 57 distinct primary outcomes showed that genetic liability to smoking (smoking initiation or lifetime smoking) was associated with increased risk of 13 circulatory system diseases, several digestive system diseases (including diverticular, gallstone, gastroesophageal reflux, and Crohn's disease, acute pancreatitis, and periodontitis), epilepsy, certain musculoskeletal system diseases (including fracture, osteoarthritis, and rheumatoid arthritis), endocrine (polycystic ovary syndrome), metabolic (type 2 diabetes) and eye diseases (including age-related macular degeneration and senile cataract) as well as cancers of the lung, head and neck, esophagus, pancreas, bladder, kidney, cervix, and ovaries, and myeloid leukemia. Smoking liability was associated with decreased risk of Parkinson's disease and prostate cancer. INTERPRETATION: This study found robust evidence that cigarette smoking causes a wide range of diseases. FUNDING: This work was supported by research grants from the Swedish Cancer Society (Cancerfonden), the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), and the Swedish Research Council (Vetenskapsrådet, 2019-00977). Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias , Pancreatite , Doença Aguda , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Neoplasias/etiologia , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos
17.
PLoS Med ; 19(7): e1004039, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35834561

RESUMO

BACKGROUND: Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits. METHODS AND FINDINGS: Observational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR). Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the "Snap" card game. Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never drinkers comprised 2.7% of the sample. Alcohol consumption was associated with markers of higher iron (χ) in putamen (ß = 0.08 standard deviation (SD) [95% confidence interval (CI) 0.06 to 0.09], p < 0.001), caudate (ß = 0.05 [0.04 to 0.07], p < 0.001), and substantia nigra (ß = 0.03 [0.02 to 0.05], p < 0.001) and lower iron in the thalami (ß = -0.06 [-0.07 to -0.04], p < 0.001). Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly. MR analyses provided weak evidence these relationships are causal. Genetically predicted alcoholic drinks weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections. Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction. Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f. <7 units (56 g). Systemic iron levels partially mediated associations of alcohol intake with brain iron. Markers of higher basal ganglia iron associated with slower executive function, lower fluid intelligence, and slower reaction times. The main limitations of the study include that χ and T2* can reflect changes in myelin as well as iron, alcohol use was self-reported, and MR estimates can be influenced by genetic pleiotropy. CONCLUSIONS: To the best of our knowledge, this study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline.


Assuntos
Alcoolismo , Análise da Randomização Mendeliana , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Bancos de Espécimes Biológicos , Encéfalo/diagnóstico por imagem , Cognição , Feminino , Humanos , Ferro , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Reino Unido/epidemiologia
18.
Int J Epidemiol ; 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35848946

RESUMO

BACKGROUND: Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life. METHODS: Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation. RESULTS: In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7). CONCLUSION: Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures.

19.
Diabetologia ; 65(10): 1664-1675, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35902387

RESUMO

AIMS/HYPOTHESIS: Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer's disease and potential causal mechanisms in the brain linking the two. METHODS: Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer's disease or Alzheimer's disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer's disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer's disease was further estimated. RESULTS: Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10-4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer's disease (OR 0.88, p=4.73×10-4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer's disease risk (OR 0.95, p=4.64×10-4) and favourable cognitive function. CONCLUSIONS/INTERPRETATION: Metformin use may cause reduced Alzheimer's disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.


Assuntos
Doença de Alzheimer , Metformina , Proteínas Quinases Ativadas por AMP/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Encéfalo , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Metformina/uso terapêutico , Pessoa de Meia-Idade
20.
Nat Genet ; 54(8): 1155-1166, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35835912

RESUMO

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.


Assuntos
Hematopoiese Clonal , Hematopoese , Transformação Celular Neoplásica , Hematopoiese Clonal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hematopoese/genética , Humanos , Mutação/genética , Fatores de Risco
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