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1.
Clin Nutr ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31564377

RESUMO

BACKGROUND & AIMS: Available epidemiological evidence on the associations of individual fatty acids (FAs) with bone mineral density and fracture risk is inconsistent and scarce. We conducted a two-sample Mendelian randomization study to explore these relationships. METHODS: Summary-level data from up to 426 824 individuals in UK Biobank for estimated bone mineral density (eBMD) derived from heel quantitative ultrasound and bone fractures were used in this study. Single-nucleotide polymorphisms associated with plasma phospholipid FA levels at genome-wide significance were exploited as instrumental variables. Analyses were conducted using the inverse-variance weighted method. RESULTS: Eight of ten FAs were associated with eBMD and fracture risk. Specifically, genetic predisposition to higher plasma α-linolenic acid, linoleic acid, palmitoleic acid, and oleic acid levels was positively associated with eBMD and inversely associated with the odds of fracture, whereas the opposite directions were observed for plasma arachidonic acid, eicosapentaenoic acid, docosapentanenoic acid, and stearic acid levels. Most of the associations were driven by single-nucleotide polymorphisms within or nearby the FADS1 and FADS2 genes, which explained the largest proportion of variance in FA levels. The associations of arachidonic acid and palmitoleic acid with eBMD remained after exclusion of the variants in the FADS1-FADS2 gene regions. FADS encodes fatty acid desaturases, which have a major role in FA metabolism. CONCLUSIONS: Genetic variations in plasma levels of several FAs were associated with eBMD and fracture risk. Variants in FADS1-FADS2 were the major determinants of the observed associations, except the associations of arachidonic acid and palmitoleic acid with eBMD.

2.
Calcif Tissue Int ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31482193

RESUMO

The causal associations of smoking and alcohol and coffee intake with fracture and bone mineral density are unknown. We investigated the associations using Mendelian randomization (MR). Summary-level data from UK Biobank for bone fractures (main outcome) (53,184 cases; 373,611 non-cases) and estimated bone mineral density (eBMD) (n = 426,824 individuals) were used. Single-nucleotide polymorphisms associated with smoking initiation (n = 378) and alcohol (n = 99) and coffee (n = 15) intake at the genome-wide significance threshold (P = 5 × 10-8) were identified from published genome-wide association studies. Univariable and multivariable inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO methods were used for statistical analyses. Genetic predisposition to smoking initiation was associated with fracture but not eBMD. The odds ratio of fracture per one-unit increase in log odds of smoking was 1.09 (95% confidence interval 1.04, 1.15; P = 8.58 × 10-4) after adjustment for alcohol intake in the multivariable MR analysis. The association remained in complementary analyses. Genetically predicted alcohol and coffee intake was not associated with fracture or eBMD. Nevertheless, genetic liability to alcohol dependence, based on variants in the ALD1B gene, was associated with fracture and lower eBMD. The odds ratio was 1.06 (95% confidence interval 1.01, 1.12; P = 0.018) per genetically predicted one-unit higher log odds of liability to alcohol dependence. This MR study strengthens the causal inference on an association between smoking and higher fracture risk but found no linear association of modestly higher alcohol and coffee intake with fracture or BMD. However, alcohol dependence may increase fracture risk.

3.
Eur Heart J ; 40(35): 2937-2938, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31520584
4.
Artigo em Inglês | MEDLINE | ID: mdl-31558414

RESUMO

BACKGROUND AND AIMS: Some observational studies have found that habitual coffee and caffeine consumption might reduce the risk of atrial fibrillation (AF). We conducted a two-sample Mendelian randomization study to explore the potential association between coffee consumption and AF. METHODS AND RESULTS: This study was based on summary-level data from the Atrial Fibrillation Consortium, including 588 190 individuals (65 446 cases and 522 744 non-cases). Nine single-nucleotide polymorphisms associated with coffee consumption at significance level of P < 5 × 10-8 were used as instrumental variables and were obtained from a genome-wide association study that included up to 375 833 individuals. The odds ratio of AF per genetically-predicted 50% increase of coffee consumption was 0.98 (95% confidence interval, 0.88, 1.10; P = 0.80) in the standard inverse-variance weighted analysis. Results were consistent in sensitivity analyses using the weighted median and MR-Egger methods, and no directional pleiotropy (P = 0.37) was observed. Moreover, complementary analyses that separated the coffee-related single-nucleotide polymorphisms based on their association with blood levels of caffeine metabolites (lower, higher, unrelated or unknown association) revealed no association with AF. CONCLUSIONS: This study does not support a causal association between habitual coffee consumption and risk of AF.

5.
Diabetes Care ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31548248

RESUMO

OBJECTIVE: We conducted a Mendelian randomization study to investigate the associations of genetically predicted serum 25-hydroxyvitamin D (S-25OHD), calcium (S-Ca), and parathyroid hormone (S-PTH) levels with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS: Seven, six, and five single nucleotide polymorphisms (SNPs) associated with S-25OHD, S-Ca, and S-PTH levels, respectively, were used as instrumental variables. Data on T2DM were available for 74,124 case subjects with T2DM and 824,006 control subjects. The inverse variance-weighted method was used for the primary analyses, and the weighted median and Mendelian randomization (MR)-Egger methods as supplementary analyses. RESULTS: Genetically predicted S-25OHD but not S-Ca and S-PTH levels were associated with T2DM in the primary analyses. For one SD increment of S-25OHD levels, the odds ratio (OR) of T2DM was 0.94 (95% CI 0.88-0.99; P = 0.029) in an analysis based on all seven SNPs and 0.90 (95% CI 0.83-0.98; P = 0.011) in an analysis based on three SNPs within or near genes involved in vitamin D synthesis. Only the association based on the SNPs involved in vitamin D synthesis remained in the weighted median analysis and no pleiotropy was detected (P = 0.153). Pleiotropy was detected in the analysis of S-Ca (P = 0.013). After correcting for this bias using MR-Egger regression, the OR of T2DM per one-SD increment of S-Ca levels was 1.41 (95% CI 1.12-1.77; P = 0.003). CONCLUSIONS: Modest lifelong higher S-25OHD levels were associated with reduced odds of T2DM, but the association was only robust for SNPs in the vitamin D synthesis pathway. The possible role of S-Ca levels for T2DM development requires further research.

6.
Circulation ; 140(9): 796-798, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31422675
7.
J Am Heart Assoc ; 8(11): e011860, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31433701

RESUMO

Background Mechanisms related to the influence of diet on the development of cardiovascular disease are not entirely understood, and protein biomarkers may help to understand these pathways. Studies of biomarkers identified with multiplex proteomic methods and dietary patterns are largely lacking. Methods and Results Dietary patterns were generated through principal component analysis in 2 population-based Swedish cohorts, the EpiHealth (EpiHealth study; n=20 817 men and women) and the SMCC (Swedish Mammography Cohort Clinical [n=4650 women]). A set of 184 protein cardiovascular disease biomarkers were measured with 2 high-throughput, multiplex immunoassays. Discovery and replication multivariable linear regression analyses were used to investigate the associations between the principal component analysis-generated dietary patterns and the cardiovascular disease-associated protein biomarkers, first in the EpiHealth (n=2240) and then in the Swedish Mammography Cohort Clinical. Four main dietary patterns were identified in the EpiHealth, and 3 patterns were identified in the Swedish Mammography Cohort Clinical. The healthy and the Western/traditional patterns were found in both cohorts. In the EpiHealth, 57 protein biomarkers were associated with 3 of the dietary patterns, and 41 of these associations were replicated in the Swedish Mammography Cohort Clinical, with effect estimates ranging from 0.057 to 0.083 (P-value range, 5.0×10-2-1.4×10-9) for each SD increase in the relative protein concentration. Independent associations were established between dietary patterns and the 21 protein biomarkers. Two proteins, myeloperoxidase and resistin, were associated with both the healthy and the light meal pattern but in opposite directions. Conclusions We have discovered and replicated independent associations between dietary patterns and 21 biomarkers linked to cardiovascular disease, which have a role in the pathways related to inflammation, endothelial and immune function, cell adhesion, and metabolism.

8.
Int J Epidemiol ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363756

RESUMO

BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium. METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries. RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH. CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.

9.
BMJ ; 366: l4410, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371314

RESUMO

OBJECTIVE: To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. DESIGN: Mendelian randomisation study. SETTING: Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). PARTICIPANTS: A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. RESULTS: A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm2, 95% confidence interval -0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. CONCLUSIONS: Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.


Assuntos
Densidade Óssea/genética , Cálcio/sangue , Predisposição Genética para Doença , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/genética , Adenosina Trifosfatases/genética , Diacilglicerol Quinase/genética , Feminino , Fator de Transcrição GATA3/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Medição de Risco , Vitamina D3 24-Hidroxilase/genética , Vitamina K Epóxido Redutases/genética
10.
Health Technol Assess ; 23(41): 1-30, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31422789

RESUMO

BACKGROUND: Symptomatic vertebral artery (VA) stenosis has been associated with a markedly increased early risk of recurrent stroke. VA stenosis can be treated with stenting; however, there are few data from randomised controlled trials evaluating the efficacy of this treatment, and recent studies in intracranial stenosis have suggested that stenting may be associated with increased risk. OBJECTIVE: The Vertebral artery Ischaemia Stenting Trial (VIST) was established to compare the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for recently symptomatic VA stenosis. DESIGN: VIST was a prospective, randomised, open, parallel, blinded end-point clinical trial. SETTING: The trial was performed in 14 hospitals in the UK. PARTICIPANTS: Recruitment began on 23 October 2008 and follow-up ended on 1 March 2016, by which time every patient had been followed up for at least 1 year. Participants had to have symptomatic vertebral stenosis of at least 50% resulting from presumed atheromatous disease. Both patients and clinicians were aware of treatment allocation; however, an independent adjudication committee, masked to treatment allocation, assessed all primary and secondary end points. INTERVENTIONS: Participants were randomly assigned (1 : 1) to either vertebral angioplasty/stenting plus BMT (n = 91) or BMT alone (n = 88). A total of 182 patients were initially enrolled; however, three patients (two who withdrew after randomisation and one who did not attend after the initial randomisation visit) did not contribute any follow-up data and were excluded. None of these three patients had outcome events. MAIN OUTCOMES AND MEASURES: The primary end point was the occurrence of fatal or non-fatal stroke in any arterial territory during follow-up. RESULTS: The median follow-up was 3.5 (interquartile range 2.1-4.7) years. Of the 61 patients who were stented, 48 (78.7%) had extracranial stenosis and 13 (21.3%) had intracranial stenosis. No perioperative complications occurred with extracranial stenting; two strokes occurred during intracranial stenting. The primary end point occurred in five patients (including one fatal stroke) in the stent group and in 12 patients (including two fatal strokes) in the medical group (giving a hazard ratio of 0.40, 95% confidence interval 0.14 to 1.13; p = 0.08), with an absolute risk reduction of 25 strokes per 1000 person-years. LIMITATIONS: The study was underpowered because it failed to reach target recruitment. The high rate of non-confirmation of stenosis in the stented group of the trial was a second limitation. CONCLUSIONS: The trial found no difference in risk of the primary end point between the two groups. FUTURE: Post hoc analysis suggested that stenting could be associated with a reduced recurrent stroke risk in symptomatic VA and further studies are now required to confirm these findings, particularly in extracranial VA stenosis where complication rates with stenting were confirmed to be very low. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95212240. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 41. See the NIHR Journals Library website for further project information. In addition, funding for the pilot phase was provided by the Stroke Association.

11.
Nutrients ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331006

RESUMO

Available evidence on the associations of dietary and circulating levels of long-chain n-3 fatty acids, which have potential antiarrhythmic properties, and other fatty acids with atrial fibrillation is conflicting and limited. We conducted a Mendelian randomization study to assess the associations between plasma phospholipid fatty acid levels and atrial fibrillation. Summary-level data of atrial fibrillation were available from 65,446 cases and 522,744 non-cases included in the Atrial Fibrillation Consortium. Sixteen single-nucleotide polymorphisms associated with ten fatty acids at significance level of p < 5 × 10-8 were identified as instrumental variables from the hitherto largest genome-wide association studies for plasma fatty acids. The fixed-effects inverse-variance weighted method was used to assess the association of individual plasma fatty acids and atrial fibrillation risk. The random-effects inverse-variance weighted method, weighted median method, and Mendelian randomization (MR)-Egger method were employed as the sensitivity analyses. Genetic predisposition to higher levels of any of the ten individual fatty acids was not associated with atrial fibrillation risk.

12.
J Clin Endocrinol Metab ; 104(11): 5595-5600, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310319

RESUMO

CONTEXT: Elevated circulating parathyroid hormone concentrations have been associated with increased risk of cardiovascular disease in observational studies, but whether the association is causal is unknown. OBJECTIVE: We used the Mendelian randomization design to test whether genetically increased serum parathyroid hormone (S-PTH) concentrations are associated with coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS: Five single-nucleotide polymorphisms robustly associated with S-PTH concentrations were used as instrumental variables to estimate the association of genetically higher S-PTH concentrations with CAD. Summary statistics data for CAD were obtained from a genetic consortium with data from 184,305 individuals (60,801 CAD cases and 123,504 noncases). MAIN OUTCOME MEASURE: OR of CAD per genetically predicted one SD increase of S-PTH concentrations. RESULTS: Genetically higher S-PTH concentration was not associated with CAD as a whole or myocardial infarction specifically (∼70% of total cases). The ORs per genetically predicted one SD increase in S-PTH concentration were 1.01 (95% CI: 0.93 to 1.09; P = 0.88) for CAD and 1.02 (95% CI: 0.94 to 1.10; P = 0.64) for myocardial infarction. The lack of association remained in various sensitivity analyses. CONCLUSION: Genetic predisposition to higher S-PTH concentrations does not appear to be an independent risk factor for CAD.

13.
Eur Heart J ; 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31195408

RESUMO

AIMS: The causal role of adiposity for several cardiovascular diseases (CVDs) is unclear. Our primary aim was to apply the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 CVDs and arterial hypertension. We also assessed the roles of fat mass and fat-free mass on the same outcomes. METHODS AND RESULTS: Single-nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instrumental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was significantly positively associated with eight outcomes, including and with decreasing magnitude of association: aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio (OR) per 1 kg/m2 increase in BMI ranged from 1.06 [95% confidence interval (CI) 1.02-1.11; P = 2.6 × 10-3] for pulmonary embolism to 1.13 (95% CI 1.05-1.21; P = 1.2 × 10-3) for aortic valve stenosis. There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes (P < 0.05). The strongest magnitude of association was with aortic valve stenosis (OR per 1 kg/m2 increase in fat mass index 1.46, 95% CI 1.13-1.88; P = 3.9 × 10-3). There was suggestive evidence of inverse associations of fat-free mass index with atrial fibrillation, ischaemic stroke, and abdominal aortic aneurysm. CONCLUSION: This study provides evidence that higher BMI and particularly fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions.

14.
Ann Neurol ; 86(3): 468-471, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237718

RESUMO

We used the Mendelian randomization design to explore the potential causal association of smoking with ischemic stroke and intracerebral hemorrhage using summary statistics data for 34,217 ischemic stroke cases and 404,630 noncases, and 1,545 cases of intracerebral hemorrhage and 1,481 noncases. Genetic predisposition to smoking initiation (ever smoking regularly), based on up to 372 single-nucleotide polymorphisms, was statistically significantly positively associated with any ischemic stroke, large artery stroke, and small vessel stroke but not cardioembolic stroke or intracerebral hemorrhage. This study provides genetic support for a causal association of smoking with ischemic stroke, particularly large artery and small vessel stroke. ANN NEUROL 2019;86:468-471.

15.
J Natl Cancer Inst ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127946

RESUMO

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38,369,156 person-years of follow-up, 1,391 gallbladder, 758 intrahepatic bile duct, 1,208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (e.g., current versus never smokers hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.34 to 2.13 and 2.22, 95%CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<0.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (e.g., >40 cigarettes/day versus never smokers HR = 2.15, 95%CI: 1.15 to 4.00; P-trend=0.001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming ≥5 versus 0 drinks/day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend=0.04). There was evidence of statistical heterogeneity between several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

16.
Int J Cancer ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

17.
Cancer Res ; 79(15): 3973-3982, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31113819

RESUMO

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

18.
19.
Circ Genom Precis Med ; 12(3): e002468, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30702347

RESUMO

BACKGROUND: Subclinical thyroid dysfunction, defined as thyroid-stimulating hormone levels outside the reference range with normal free thyroxine levels in asymptomatic patients, is associated with alterations in cardiac hemodynamics. We used Mendelian randomization to assess the role of thyroid dysfunction for cardiovascular disease (CVD). METHODS: Single-nucleotide polymorphisms associated with thyroid function were identified from a genome-wide association meta-analysis in up to 72 167 individuals. Data for genetic associations with CVD were obtained from meta-analyses of genome-wide association studies of atrial fibrillation (n=537 409 individuals), coronary artery disease (n=184 305 individuals), and ischemic stroke (n=438 847) as well as from the UK Biobank (n=367 703 individuals). RESULTS: Genetically predicted thyroid-stimulating hormone levels and hyperthyroidism were statistically significantly associated with atrial fibrillation but no other CVDs at the Bonferroni-corrected level of significance ( P<7.8×10-4). The odds ratios of atrial fibrillation were 1.15 (95% CI, 1.11-1.19; P=2.4×10-14) per genetically predicted 1 SD decrease in thyroid-stimulating hormone levels and 1.05 (95% CI, 1.03-1.08; P=5.4×10-5) for genetic predisposition to hyperthyroidism. Genetically predicted free thyroxin levels were not statistically significantly associated with any CVD. CONCLUSIONS: This Mendelian randomization study supports evidence for a causal association of decreased thyroid-stimulating hormone levels in the direction of a mild form of hyperthyroidism with an increased risk of atrial fibrillation but no other CVDs.

20.
Ann Neurol ; 85(4): 495-501, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30785218

RESUMO

OBJECTIVE: Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. METHODS: We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). RESULTS: Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. INTERPRETATION: These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.

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