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1.
J Am Heart Assoc ; 8(20): e012556, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31576770

RESUMO

Background Active commuting is related to a higher level of physical activity but more exposure to ambient air pollutants. With the rather serious air pollution in urban China, we aimed to examine the association between active commuting and risk of incident cardiovascular disease in the Chinese population. Methods and Results A total of 104 170 urban commuters without major chronic diseases at baseline were included from China Kadoorie Biobank. Self-reported commuting mode was defined as nonactive commuting, work at home or near home, walking, and cycling. Multivariable Cox regression was used to examine associations between commuting mode and cardiovascular disease. Overall, 47.2% of the participants reported nonactive commuting, 13.4% reported work at home or work near home, 20.1% reported walking, and 19.4% reported cycling. During a median follow-up of 10 years, we identified 5374 incidents of ischemic heart disease, 664 events of hemorrhagic stroke, and 4834 events of ischemic stroke. After adjusting for sex, socioeconomic status, lifestyle factors, sedentary time, body mass index, comorbidities, household air pollution, passive smoking, and other domain physical activity, walking (hazard ratio, 0.90; 95% CI, 0.84-0.96) and cycling (hazard ratio, 0.81; 95% CI, 0.74-0.88) were associated with a lower risk of ischemic heart disease than nonactive commuting. Cycling was associated with a lower risk of ischemic stroke (hazard ratio, 0.92; 95% CI, 0.84-1.00). No significant association was found of walking or cycling with hemorrhagic stroke. The associations of commuting mode with major cardiovascular disease were consistent among men and women and across different levels of other domain physical activity. Conclusions In urban China, cycling was associated with a lower risk of ischemic heart disease and ischemic stroke. Walking was associated with a lower risk of ischemic heart disease.

2.
Nat Commun ; 10(1): 4330, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551420

RESUMO

Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10-14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.

3.
Diabetes ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399431

RESUMO

In observational studies, type 2 diabetes is associated with 2- to 4-fold higher risks of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank, we examined associations of genetically-predicted type 2 diabetes with CVD among ∼160,000 participants, to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (OR 1.17 [95% CI 1.05, 1.29] per 1 unit higher log-odds of type 2 diabetes; n=6,819), and elevated risk of ischaemic stroke (IS) (1.08 [1.02, 1.14]; n=17,097), non-lacunar IS (1.09 [1.03, 1.16]; n=13,924) and major coronary event (1.12 [1.02, 1.23]; n= 5,081). There was no significant association with lacunar IS (1.03 [0.91, 1.16], n=3,173) or intracerebral haemorrhage (ICH) (1.01 [0.94, 1.10], n=6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB (p for heterogeneity>0.3), and with the associations of type 2 diabetes with IS, ICH and coronary heart disease in two-sample Mendelian randomisation analyses based on summary statistics from European population GWAS (p for heterogeneity>0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.

4.
BMC Med ; 17(1): 160, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31466528

RESUMO

BACKGROUND: Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease. However, it is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. Therefore, we examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans. METHODS: We used a Mendelian randomisation (MR) design in the China Kadoorie Biobank, the Copenhagen City Heart Study, and the Copenhagen General Population Study. The 25(OH)D-related genetic variants in the CYP2R1 and DCHR7 genes were genotyped in 99,012 Chinese adults and 106,911 Danish adults. RESULTS: In Chinese adults, plasma 25(OH)D levels were not significantly associated with cause-specific vascular disease or mortality, with the exception of intracerebral haemorrhage (HR, 1.09 [95% CI, 1.01,1.18] per 25 nmol/L higher plasma 25(OH)D). In Europeans, plasma 25(OH)D levels were inversely associated with all types of vascular diseases and mortality. However, MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with cause-specific vascular diseases, or mortality in both Chinese and European adults. In addition, each 25 nmol/L higher 25(OH)D was observationally associated with lower total cholesterol and low-density lipoprotein cholesterol levels, but higher high-density lipoprotein cholesterol levels. Likewise, MR analysis showed that 25(OH)D levels were not causally associated with lipids in both Chinese and European adults after Bonferroni correction. CONCLUSIONS: We found no evidence to support that genetically increased 25(OH)D was associated with a lower risk of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels in both Chinese and European adults. These results suggest that the inverse associations of vitamin D with vascular disease could be the result of confounding.

5.
Circ Genom Precis Med ; 12(9): 386-396, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31461308

RESUMO

BACKGROUND: Physical inactivity and sedentary behavior are associated with higher risk of cardiovascular disease (CVD). Little is known about the relevance of circulating metabolites for these associations. METHODS: A nested case-control study within the prospective China Kadoorie Biobank included 3195 incident CVD cases (2057 occlusive CVD and 1138 intracerebral hemorrhage) and 1465 controls aged 30 to 79 years without prior CVD or statin use at baseline. Nuclear magnetic resonance spectroscopy was used to measure 225 metabolic markers and derived traits in baseline plasma samples. Linear regression was used to relate self-reported physical activity and sedentary leisure time to biomarkers, adjusting for potential confounders. These were contrasted with associations of biomarkers with occlusive CVD risk. RESULTS: Physical activity and sedentary leisure time were associated with >100 metabolic markers, with patterns of associations generally mirroring each other. Physical activity was inversely associated with very low and low-density and positively with large and very large HDL (high-density lipoprotein) particle concentrations. Physical activity was also inversely associated with alanine, glucose, lactate, acetoacetate, and the inflammatory marker glycoprotein acetyls. In general, associations of physical activity and sedentary leisure time with specific metabolic markers were directionally consistent with the associations of these metabolic markers with occlusive CVD risk. Overall, metabolic markers potentially explained ≈70% of the protective associations of physical activity and ≈50% of the positive associations of sedentary leisure time with occlusive CVD. CONCLUSIONS: Among Chinese adults, physical activity and sedentary behavior have opposing associations with a diverse range of circulating metabolites, which may partially explain their associations with CVD risk.

6.
J Am Heart Assoc ; 8(15): e011919, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31364443

RESUMO

Background Lean body mass has been identified as a key determinant of left ventricular mass and wall thickness. However, the importance of lean body mass or other body-size measures as normative determinants of carotid intima-media thickness (cIMT), a widely used early indicator of atherosclerosis, has not been well established. Methods and Results Carotid artery ultrasound measurements of cIMT and carotid artery plaque burden (derived from plaque number and maximum size) and measurements of body size, including height, body mass index, weight, body fat proportion, and lean body mass ([1-body fat proportion]×weight), were recorded in 25 020 participants from 10 regions of China. Analyses were restricted to a healthy younger subset (n=6617) defined as never or long-term ex-regular smokers aged <60 years (mean age, 50) without previous ischemic heart disease, stroke, diabetes mellitus, or hypertension and with plasma non-high-density lipoprotein cholesterol <4 mmol/L. Among these 6617 participants, 86% were women (because most men smoked) and 9% had carotid artery plaque. In both women and men separately, lean body mass was strongly positively associated with cIMT, but was not associated with plaque burden: overall, each 10 kg higher lean body mass was associated with a 0.03 (95% CI, 0.03-0.04) mm higher cIMT (P=5×10-33). Fat mass, height, and other body-size measures were more weakly associated with cIMT. Conclusions The strong association of lean body mass with cIMT, but not with plaque burden, in healthy adults suggests a normative relationship rather than reflecting atherosclerotic pathology. Common mechanisms may underlie the associations of lean body mass with cIMT and with nonatherosclerotic vascular traits.

7.
Lancet Respir Med ; 7(10): 881-891, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.

8.
JAMA Netw Open ; 2(5): e194873, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31150080

RESUMO

Importance: A better understanding of the role of atherosclerosis in the development of ischemic stroke subtypes could help to improve strategies for prevention of stroke worldwide. Objective: To assess the role of carotid atherosclerosis in the association between major cardiovascular risk factors and ischemic stroke subtypes. Design, Setting, and Participants: The prospective China Kadoorie Biobank cohort study was conducted in the general population of 5 urban and 5 rural areas in China, with a baseline survey obtained between June 2004 and July 2008. A random sample of 23 973 participants with no history of cardiovascular disease at enrollment who had carotid artery ultrasonographic measurements recorded at a resurvey from September 2013 to June 2014 were included. Data analysis was performed from July 1, 2016, to April 10, 2019. Exposures: Major cardiovascular risk factors (ie, blood pressure [BP], blood lipid levels, smoking, and diabetes). Main Outcomes and Measures: Carotid ultrasonographic measures of plaque burden (derived from number and maximum size of carotid artery plaques at resurvey) and first ischemic stroke during follow-up (n = 952), with subtyping (data release, August 2018) as lacunar (n = 263), probable large artery (n = 193), probable cardioembolic (n = 66), or unconfirmed (n = 430). Associations between cardiovascular risk factors, carotid plaque burden, and ischemic stroke subtypes were adjusted for age, sex, and geographic area. Results: The 23 973 participants in the study had a mean (SD) age of 50.6 (10.0) years, and 14 833 (61.9%) were women. Systolic BP had a stronger association (odds ratio [OR] per SD, 1.51; 95% CI, 1.42-1.61) than plaque burden (OR per SD, 1.34; 95% CI, 1.26-1.44) with ischemic stroke, and the associations of systolic BP with each subtype of ischemic stroke were modestly attenuated by adjustment for plaque burden. After adjustment for BP, plaque burden had a stronger association with probable large artery stroke (OR, 1.43; 95% CI, 1.24-1.63) than with lacunar stroke (OR, 1.25; 95% CI, 1.10-1.43) but was not associated with probable cardioembolic stroke (OR, 1.06; 95% CI, 0.83-1.36). Conclusions and Relevance: Although BP was an important risk factor for all ischemic stroke subtypes, carotid atherosclerosis was an important risk factor only for large artery and lacunar strokes, suggesting that drug treatments targeting atherosclerosis may reduce the risk of stroke subtypes to different extents.

9.
Lancet ; 394(10196): 407-418, 2019 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-31230828

RESUMO

BACKGROUND: Asthma is a common chronic airway disease worldwide. Despite its large population size, China has had no comprehensive study of the national prevalence, risk factors, and management of asthma. We therefore aimed to estimate the national prevalence of asthma in a representative sample of the Chinese population. METHODS: A representative sample of 57 779 adults aged 20 years or older was recruited for the national cross-sectional China Pulmonary Health (CPH) study using a multi-stage stratified sampling method with parameters derived from the 2010 census. Ten Chinese provinces, representative of all socioeconomic settings, from six geographical regions were selected, and all assessments were done in local health centres. Exclusion criteria were temporary residence, inability to take a spirometry test, hospital treatment of cardiovascular conditions or tuberculosis, and pregnancy and breastfeeding. Asthma was determined on the basis of a self-reported history of diagnosis by a physician or by wheezing symptoms in the preceding 12 months. All participants were assessed with a standard asthma questionnaire and were classed as having or not having airflow limitation through pulmonary function tests before and after the use of a bronchodilator (400 µg of salbutamol). Risk factors for asthma were examined by multivariable-adjusted analyses done in all participants for whom data on the variables of interest were available. Disease management was assessed by the self-reported history of physician diagnosis, treatments, and hospital visits in people with asthma. FINDINGS: Between June 22, 2012, and May 25, 2015, 57 779 participants were recruited into the CPH study. 50 991 (21 446 men and 29 545 women) completed the questionnaire survey and had reliable post-bronchodilator pulmonary function test results and were thus included in the final analysis. The overall prevalence of asthma in our sample was 4·2% (95% CI 3·1-5·6), representing 45·7 million Chinese adults. The prevalence of asthma with airflow limitation was 1·1% (0·9-1·4), representing 13·1 million adults. Cigarette smoking (odds ratio [OR] 1·89, 95% CI 1·26-2·84; p=0·004), allergic rhinitis (3·06, 2·26-4·15; p<0·0001), childhood pneumonia or bronchitis (2·43, 1·44-4·10; p=0·002), parental history of respiratory disease (1·44, 1·02-2·04; p=0·040), and low education attainment (p=0·045) were associated with prevalent asthma. In 2032 people with asthma, only 28·8% (95% CI 19·7-40·0) reported ever being diagnosed by a physician, 23·4% (13·9-36·6) had a previous pulmonary function test, and 5·6% (3·1-9·9) had been treated with inhaled corticosteroids. Furthermore, 15·5% (11·4-20·8) people with asthma reported at least one emergency room visit and 7·2% (4·9-10·5) at least one hospital admission due to exacerbation of respiratory symptoms within the preceding year. INTERPRETATION: Asthma is prevalent but largely undiagnosed and undertreated in China. It is crucial to increase the awareness of asthma and disseminate standardised treatment in clinical settings to reduce the disease burden. FUNDING: National Key R&D Program of China, Ministry of Science and Technology of China; the Special Research Foundation for Public Welfare of Health, Ministry of Health of China; the Chinese National Research Program for Key Issues in Air Pollution Control; and the National Natural Science Foundation of China.


Assuntos
Asma/tratamento farmacológico , Asma/epidemiologia , Bronquite/epidemiologia , Fumar Cigarros/epidemiologia , Pneumonia/epidemiologia , Rinite Alérgica/epidemiologia , Administração por Inalação , Corticosteroides/uso terapêutico , Adulto , Asma/etiologia , Bronquite/complicações , China/epidemiologia , Fumar Cigarros/efeitos adversos , Estudos Transversais , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/complicações , Prevalência , Rinite Alérgica/complicações , Fatores de Risco , Inquéritos e Questionários
10.
Diabetologia ; 62(8): 1420-1429, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152186

RESUMO

AIMS/HYPOTHESIS: China has undergone rapid socioeconomic transition accompanied by lifestyle changes that are expected to have a profound impact on the health of its population. However, there is limited evidence from large nationwide studies about the relevance of socioeconomic status (SES) to risk of diabetes. We describe the associations of two key measures of SES with prevalent and incident diabetes in Chinese men and women. METHODS: The China Kadoorie Biobank study included 0.5 million adults aged 30-79 years recruited from ten diverse areas in China during 2004-2008. SES was assessed using the highest educational level attained and annual household income. Prevalent diabetes was identified from self-report and plasma glucose measurements. Incident diabetes was identified from linkage to disease and death registries and national health insurance claim databases. We estimated adjusted ORs and HRs for prevalent and incident diabetes associated with SES using logistic and Cox regression models, respectively. RESULTS: At baseline, 30,066 (5.9%) participants had previously diagnosed (3.1%) or screen-detected (2.8%) diabetes among 510,219 participants included for cross-sectional analyses. There were 480,153 people without prevalent diabetes at baseline, of whom 9544 (2.0%) had new-onset diabetes during follow-up (median 7 years). Adjusted ORs (95% CIs) for prevalent diabetes, comparing highest vs lowest educational level, were 1.21 (1.09, 1.35) in men and 0.69 (0.63, 0.76) in women; for incident diabetes, the corresponding HRs were 1.27 (1.07, 1.51) and 0.80 (0.67, 0.95), respectively. For household income, the adjusted ORs for prevalent diabetes, comparing highest vs lowest categories, were 1.45 (1.34, 1.56) in men and 1.26 (1.19, 1.34) in women; for incident diabetes, the HRs were 1.36 (1.19, 1.55) and 1.06 (0.95, 1.17), respectively. CONCLUSIONS/INTERPRETATION: Among Chinese adults, the associations between education and diabetes prevalence and incidence differed qualitatively between men and women, whereas higher household income was positively associated with diabetes prevalence and incidence in both sexes, with a stronger relationship in men than in women.

11.
Cancer Cell ; 35(6): 916-931.e9, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185214

RESUMO

Diffuse large B cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B cells. Here, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted class I sirtuin inhibitor, YC8-02, which phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.

12.
BMC Geriatr ; 19(1): 168, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200646

RESUMO

BACKGROUND: Self-rated health (SRH) have been widely used as a valid indicator of health status at the population and individual level. We aimed to investigate the distribution and correlates of global SRH and age-comparative SRH in elderly Chinese. METHODS: Survey of 57,693 men and 67,089 women aged 60 years and above was conducted in five rural (Gansu, Sichuan, Hunan, Henan, Zhejiang) and five urban areas (Heilongjiang, Shandong, Jiangsu, Guangxi, Hainan) in China between 2004 and 2008. Logistic regression models were used to calculate the relations of different factors with global SRH and age-comparative SRH. RESULTS: Among the participants, 38.33% reported their global SRH as good or excellent while 61.67% as fair or poor, and 17.70% reported better age-comparative SRH while 17.99% as worse. In the multivariate model, compared to women, men tended to report a good global SRH and better age-comparative SRH, urban residents tend to report good global SRH and better age-comparative SRH. The socioeconomic and health behavior factors that were associated with good global SRH and better age-comparative SRH (with varying strengths of association) included: high educational level, high household income, house ownership, quitting smoking by own choices, occasional and current alcohol drinking, overweight, and high physical activity level. The factors that were associated with poor global SRH and worse age-comparative SRH included: quitting smoking by illness, former drinking, underweight, and weight lost ≥2.5 kg in the previous year. CONCLUSIONS: We found a moderate level of good global SRH and a low level of better age-comparative SRH among elderly Chinese. We identified a number of demographic, socioeconomic and health behavior factors that were related to SRH measures. Our study emphasizes the importance of incorporating both global and age-comparative SRH measures in future studies, and considering gender inequalities and urban/rural disparity, as well as socioeconomic status and health behaviors as important modifiers of health.

13.
JAMA Netw Open ; 2(6): e195718, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31199446

RESUMO

Importance: Hepatitis B virus (HBV) has been identified as a major risk factor for hepatocellular carcinoma. However, the associations between HBV infection and other cancer types are not well understood. Objective: To assess the associations between chronic HBV infection and risk of all cancer types. Design, Setting, and Participants: This population-based study involved 3 cohorts in China. The China Kadoorie Biobank (CKB) prospective cohort study, conducted between June 2004 and July 2008, used a dipstick assay for detection of serum hepatitis B surface antigen (HBsAg) among 496 732 participants to determine the association between HBV infection and risk of all cancer types. Two cohort studies were used to validate the associations by applying more precise serum HBsAg detection assays: the Qidong cohort (37 336 participants enrolled from November 2007 to April 2011) and the Changzhou nested case-control study (17 723 participants enrolled from June 2004 to September 2005). A total of 97 samples of stomach cancer tissues, 10 samples of pancreatic cancer tissues, and 9 samples of lung cancer tissues were included to assess the presence of HBV replication and expression. Statistical analysis was performed from December 2016 to October 2018. Exposures: Serum HBsAg status in the population-based stage and HBV DNA status, the expression of hepatitis B X protein, and hepatitis B core antibody (anti-HBc) in the tissue-based stage. Main Outcomes and Measures: Incidence of all cancer types during follow-up. Results: In the CKB cohort, the mean (SD) age of the 496 732 participants was 51.5 (10.7) years; 59.0% of the participants were women. After 4.4 million person-years of follow-up, participants who were HBsAg seropositive (n = 15 355) had a higher risk of hepatocellular carcinoma (hazard ratio [HR], 15.77; 95% CI, 14.15-17.57), stomach cancer (HR, 1.41; 95% CI, 1.11-1.80), colorectal cancer (HR, 1.42; 95% CI, 1.12-1.81), oral cancer (HR, 1.58; 95% CI, 1.01-2.49), pancreatic cancer (HR, 1.65; 95% CI, 1.03-2.65), and lymphoma (HR, 2.10; 95% CI, 1.34-3.31) when compared with participants who were HBsAg seronegative (n = 481 377). Because of the limitation of sample size, only associations of HBV infection with hepatocellular carcinoma and stomach cancer were validated in the Qidong cohort (hepatocellular carcinoma: HR, 17.51; 95% CI, 13.86-22.11; stomach cancer: HR, 2.02; 95% CI, 1.24-3.29); the Changzhou nested case-control study validated only an association between HBV infection and stomach cancer (odds ratio, 1.76; 95% CI, 1.04-2.98). Moreover, among 22 participants with stomach cancer from the Qidong cohort who were anti-HBc seropositive, 12 samples (54.5%) of cancer tissues were HBV DNA positive, while among 25 participants with stomach cancer who were anti-HBc seronegative, no HBV DNA was detected. The same negative and positive rate was observed in the validation set from Zhejiang Tumor Hospital (19 of 35 samples [54.3%] were HBV DNA positive). Moreover, among the 8 patients with stomach cancer from the Qidong cohort who were anti-HBc seropositive, anti-HBc and hepatitis B X protein were expressed in all of their stomach cancer tissue samples. The same phenomenon was observed in the patients with pancreatic cancer but not in the patients with lung cancer, which was consistent with the population-based results of the CKB cohort. Conclusions and Relevance: This study found that HBV infection was also associated with the risk of nonliver cancer, especially digestive system cancers among adults in China.

14.
Eur J Epidemiol ; 34(8): 753-763, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152367

RESUMO

Current experimental and epidemiological studies provide inconsistent evidence toward the association between tea consumption and cancer incidence. We investigated whether tea consumption was associated with the incidence of all cancers and six leading types of cancer (lung cancer, stomach cancer, colorectal cancer, liver cancer, female breast cancer and cervix uteri cancer) among 455,981 participants aged 30-79 years in the prospective cohort China Kadoorie Biobank. Tea consumption was assessed at baseline (2004-2008) with an interviewer-administered questionnaire. Cancer cases were identified by linkage to the national health insurance system. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In the present population, daily tea consumers were more likely to be current smokers and daily alcohol consumers. 22,652 incident cancers occurred during 10.1 years follow-up (5.04 cases/1000 person-years). When we restricted analyses to non-smokers and non-excessive alcohol consumers to minimize confounding, tea consumption was not associated with all cancers (daily consumers who added tea leaves > 4.0 g/day vs. less-than-weekly consumers: HR, 1.03; 95%CI, 0.93-1.13), lung cancer (HR, 1.08; CI, 0.84-1.40), colorectal cancer (HR, 1.08; CI, 0.81-1.45) and liver cancer (HR, 1.08; CI, 0.75-1.55), yet might be associated with increased risk of stomach cancer (HR, 1.46; CI, 1.07-1.99). In both less-than-daily and daily tea consumers, all cancer risk increased with the amount of tobacco smoked or alcohol consumed. Our findings suggest tea consumption may not provide preventive effect against cancer incidence.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Cafeína/efeitos adversos , Neoplasias/epidemiologia , Neoplasias/etiologia , Medição de Risco/métodos , Chá/efeitos adversos , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , China/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , População Rural , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia , Fumar Tabaco/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia
15.
Mol Cancer ; 18(1): 92, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072393

RESUMO

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMMB promoted liver metastasis. It was unknown whether RHAMMB is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMMA and RHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMMB, but not RHAMMA, was significantly upregulated in liver metastases. RHAMMB was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMMB was substantially higher than RHAMMA in pancreatic ductal adenocarcinoma (PDAC). RHAMMB, but not RHAMMA, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMMB-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMMB, but not RHAMMA, in promoting PNET metastasis in part through EGFR signaling. RHAMMB can thus serve as a prognostic factor for pancreatic cancer.

17.
Int J Cancer ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31115907

RESUMO

High body mass index (BMI) has been associated with an increased risk of several cancers. Evidence relating body fatness, especially based on different anthropometric measures, to risk of major cancers in China from prospective cohort studies is lacking. The prospective China Kadoorie Biobank study recruited 0.5 million adults aged 30-79 years from 10 diverse areas across China during 2004-2008, recording 21,474 incident cancers during 8.95 years of follow-up. BMI, body fat percentage (BFP), waist circumference (WC) and waist-to-hip ratio (WHR) were measured at baseline. We assessed the associations of body fatness with 15 major cancers by calculating Cox regression yielded adjusted hazard ratios (HRs). Each 5 kg/m2 increase in BMI was associated with an increased risk of endometrial (HR, 2.01; 95% CI, 1.72-2.35), postmenopausal breast (HR, 1.29; 95% CI, 1.18-1.40), colorectal (HR, 1.17; 95% CI, 1.10-1.25) and cervical (HR, 1.15; 95% CI, 1.03-1.29) cancer, whereas it was associated with a reduced risk of esophageal (HR, 0.73; 95% CI, 0.67-0.79), lung (HR, 0.78; 95% CI, 0.74-0.82), liver (HR, 0.85; 95% CI, 0.79-0.92) and gastric (HR, 0.88; 95% CI, 0.82-0.94) cancer. Significant linear trends of BMI-cancer associations were observed, excluding for lung, gastric and cervical cancer (both overall and nonlinear p < 0.05). The relation between BFP, WC and WHR and the above cancers was similar to that of BMI. Our study indicates that either high or low body fatness contributes to the incidence of different types of cancer in China.

18.
Leuk Lymphoma ; : 1-5, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31120355

RESUMO

In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1-12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m2 (dose levels 1, 2, 3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1-12 plus bortezomib 1.0 mg/m2 on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents.

19.
Lancet ; 393(10183): 1831-1842, 2019 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-30955975

RESUMO

BACKGROUND: Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink). METHODS: The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161 498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake. FINDINGS: 33% (69 897/210 205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week-ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36-1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13-1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78-1·18, p=0·69). Usual alcohol intake in current drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction. INTERPRETATION: Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction. FUNDING: Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust.


Assuntos
Álcool Desidrogenase/metabolismo , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Doenças Cardiovasculares/genética , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hemorragia Cerebral/epidemiologia , China/epidemiologia , Extremo Oriente/epidemiologia , Feminino , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia
20.
Ann Clin Transl Neurol ; 6(4): 624-632, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31019987

RESUMO

Objective: The objectives of this study were to compare the risks of Parkinson's disease among those with versus those without prior stroke or heart disease at baseline in a prospective study of 0.5 million adults in China, and to examine associations of cardiovascular disease risk factors (cigarette smoking, hypertension, diabetes, obesity) with risk of Parkinson's disease. Methods: During an average of 11.5 years of follow-up of 503,497 middle-aged participants in the China Kadoorie Biobank study, 603 incident cases were hospitalized with a diagnosis of Parkinson's disease. Cox proportional hazards models were used to assess associations of history of heart disease or stroke with Parkinson's disease in all participants, and of cardiovascular disease risk factors with Parkinson's disease in a subset without prior cardiovascular disease. Results: In this population the incidence rate of Parkinson's disease (mean [SD] age of cases, 61 [10] years) was 13.3 (95% confidence interval: 12.3-14.4) per 100,000 person-years. Incidence increased with age, and was higher in men than in women, and in urban than in rural residents. Prior stroke was associated with about twofold higher risk of Parkinson's disease (hazard ratio 1.94; 1.39-2.69). After adjustment for confounders in those without prior cardiovascular disease, a 5 kg/m2 higher body mass index was associated with 17% (1.17; 1.03-1.34: P = 0.019) higher risk of Parkinson's disease, but neither hypertension, diabetes, nor current cigarette smoking was significantly associated with Parkinson's disease. Interpretation: Prior stroke and adiposity were each associated with higher risks of Parkinson's disease, but none of the other cardiovascular disease risk factors were significantly associated with Parkinson's disease in this population.

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