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1.
Int J Epidemiol ; 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31377785

RESUMO

BACKGROUND: Lifetime use of bituminous ('smoky') coal is associated with nearly a 100-fold higher risk of lung cancer mortality compared with anthracite ('smokeless') coal use in rural Xuanwei, China, among women. Risk of mortality from ischaemic heart disease (IHD) and stroke for these coal types has not been evaluated. METHODS: A cohort of 16 323 non-smoking women in Xuanwei, who were lifetime users of either smoky or smokeless coal, were followed up from 1976 to 2011. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) to evaluate lifetime use of coal types and stoves in the home in relation to risk of IHD and stroke mortality. RESULTS: Among lifetime users of smokeless coal, higher average exposure intensity (≥4 tons/year vs <2.5 tons/year, HR = 7.9, 95% CI = 3.5-17.8; Ptrend =<0.0001) and cumulative exposure (>64 ton-years vs ≤28 ton-years, HR = 6.5, 95% CI = 1.5-28.3; Ptrend =0.003) during follow-up and over their lifetime was associated with increased IHD mortality, and ventilated stove use dramatically reduced this risk (HR = 0.2, 95% CI 0.1-0.5). Higher cumulative exposure to smoky coal during follow-up showed positive associations with IHD mortality, but the evidence for other metrics was less consistent compared with associations with smokeless coal use. CONCLUSIONS: Higher use of smokeless coal, which is burned throughout China and is generally regarded to be a cleaner fuel type, is associated with IHD mortality. Use of cleaner fuels or stove interventions may be effective in reducing the increasing burden of IHD in developing regions that currently rely on smokeless coal for cooking and heating.

2.
BMJ Open ; 9(8): e026225, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31444178

RESUMO

OBJECTIVE: To study the association of educational level and risk of death from all causes, cardiovascular disease (CVD) and cancer among Asian populations. DESIGN: A pooled analysis of 15 population-based cohort studies. SETTING AND PARTICIPANTS: 694 434 Asian individuals from 15 prospective cohorts within the Asia Cohort Consortium. INTERVENTIONS: None. MAIN OUTCOME MEASURES: HRs and 95% CIs for all-cause mortality, as well as for CVD-specific mortality and cancer-specific mortality. RESULTS: A total of 694 434 participants (mean age at baseline=53.2 years) were included in the analysis. During a mean follow-up period of 12.5 years, 103 023 deaths were observed, among which 33 939 were due to cancer and 34 645 were due to CVD. Higher educational levels were significantly associated with lower risk of death from all causes compared with a low educational level (≤primary education); HRs and 95% CIs for secondary education, trade/technical education and ≥university education were 0.88 (0.85 to 0.92), 0.81 (0.73 to 0.90) and 0.71 (0.63 to 0.80), respectively (ptrend=0.002). Similarly, HRs (95% CIs) were 0.93 (0.89 to 0.97), 0.86 (0.78 to 0.94) and 0.81 (0.73 to 0.89) for cancer death, and 0.88 (0.83 to 0.93), 0.77 (0.66 to 0.91) and 0.67 (0.58 to 0.77) for CVD death with increasing levels of education (both ptrend <0.01). The pattern of the association among East Asians and South Asians was similar compared with ≤primary education; HR (95% CI) for all-cause mortality associated with ≥university education was 0.72 (0.63 to 0.81) among 539 724 East Asians (Chinese, Japanese and Korean) and 0.61 (0.54 to 0.69) among 154 710 South Asians (Indians and Bangladeshis). CONCLUSION: Higher educational level was associated with substantially lower risk of death among Asian populations.

3.
J Urol ; : 101097JU0000000000000493, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31430246

RESUMO

INTRODUCTION: High animal protein intake is a risk factor for nephrolithiasis. Whether plant-based sources of protein associate with kidney stone risk is not well studied. We examined the association of animal and plant protein intakes and risk of incident kidney stones in Shanghai, China. METHODS/MATERIALS: Dietary intakes were obtained from a validated food frequency questionnaire at baseline. Self-reported stone events were ascertained at baseline and during the follow-up visits. Multivariable Cox regression models were used to evaluate the associations of protein intakes with incident stone risk. RESULTS: During 319,211 and 696,950 person-years of follow-up, 1,451 men and 1,202 women reported incident stones. The average intakes of animal and plant protein standardized to 2,000 Kcal were respectively 31.3±13.7 and 48.4±7.2 (g/d) for women and 30.8±13.3 and 51.3±7.6 for men. On multivariable analysis, participants in the highest quintiles of animal (HR= 1.16[1.01-1.32], P= 0.03) and non-dairy animal protein intakes (HR= 1.14[1.01-1.30], P= 0.04) showed an increased risk of incident stones compared to the lowest quintiles. The highest intake quintiles of the animal to plant protein ratios (HR= 1.17[1.03-1.33], P= 0.02), and non-dairy animal to plant protein ratios (HR= 1.20[1.06-1.36], P= 0.005) were positively associated with stone risk compared to the lowest quintile. No association was observed with plant protein intakes (P trend= 0.14). CONCLUSIONS: Among this population of relatively low animal protein and high plant protein intakes, greater animal protein intake is associated with kidney stone risk. Increasing the proportion of plant protein relative to animal protein appears protective against the risk.

4.
Eur J Prev Cardiol ; : 2047487319867500, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382808

RESUMO

AIMS: The aim of this study was to investigate whether the Western dietary guidelines on fruit and vegetable intake are associated with blood pressure parameters and hypertension among Vietnamese adults. METHODS: Participants included 1384 women and 1049 men aged 18-69 years from the 2015 Vietnam national survey on risk factors of non-communicable diseases. Associations between dietary intake score based on the Dietary Approaches to Stop Hypertension (DASH) guidelines and World Health Organization recommendations on fruit and vegetable consumption and blood pressure parameters and hypertension were evaluated by multivariate regression analyses. RESULTS: Approximately 17.0% and 40.1% of participants met the respective definitions of hypertension according to Joint National Committee 7 (JNC7) and 2017 American College of Cardiology/American Heart Association (ACC/AHA) Hypertension Guideline. Highest tertiles of DASH scores for fruit intake were significantly associated with increased blood pressure parameters, particularly in women. Hypertension was associated with DASH score for fruit intake with odds ratios and 95% confidence intervals for tertiles 2-3 versus tertile 1: 1.31 (0.98, 1.76) and 1.43 (1.05, 1.93) for JNC7; 1.26 (1.01, 1.58) and 1.31 (1.04, 1.66) for 2017 ACC/AHA guideline (all p-trend <0.05). No association with blood pressure parameters and hypertension was observed for DASH score for vegetable intake and meeting World Health Organization recommendations for fruit and vegetable intake. CONCLUSION: We found an unexpected positive association between DASH score for fruit intake and blood pressure parameters and hypertension among Vietnamese adults. More research is needed in this population to understand the relationship between vegetable and fruit intake with hypertension before a firm conclusion and recommendation are made.

5.
J Surg Res ; 245: 265-272, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31421372

RESUMO

BACKGROUND: Although insurance and race-based survival disparities in colon cancer are well studied, little is known regarding how these survival disparities are impacted by type of treating facility. MATERIALS AND METHODS: This is a retrospective cohort study of 433,997 patients diagnosed with colon adenocarcinoma using the National Cancer Database (NCDB). Using Cox proportional hazard analyses, we assessed overall survival (OS) as a function of race, insurance status, and treating facility, after adjusting for demographic and clinical factors. We also assessed differences in OS according to race and insurance status stratified by treating facility type. RESULTS: OS was significantly diminished for blacks (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.07-1.10; P < 0.001) and increased for patients of other race (primarily Asians; HR, 0.76; 95% CI, 0.74-0.78) compared with whites. Patients with private insurance had improved OS compared with uninsured (HR, 1.28; 95% CI, 1.25-1.31; P < 0.001), Medicaid (HR, 1.35; 95% CI, 1.33-1.38; P < 0.001) and Medicare (HR, 1.13, 95% CI, 1.12-1.15; P < 0.001) patients. Compared with patients treated at comprehensive community programs, patients treated at academic centers (ACs) had improved OS (HR, 0.86; 95% CI, 0.85-0.88; P < 0.001). When stratified by type of treating facility, racial disparities were not mitigated for patients treated at ACs compared with other facilities (P = 0.266 for interaction). At ACs, patients with Medicaid had persistent OS disparities compared with patients with private insurance (HR, 1.12; 95% CI, 1.09-1.15; P < 0.001), although these disparities were significantly diminished compared with patients treated at other facilities (HR, 1.41; 95% CI, 1.38-1.45; P < 0.001). CONCLUSIONS: Other race, private insurance, and treatment at AC were independently associated with improved OS in patients with colon cancer. Medicaid-based, but not race-based, survival disparities are reduced at ACs compared with other facilities.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31399476

RESUMO

BACKGROUND: To date, few epidemiological studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma (MM) in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of MM mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium. METHODS: The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between BMI, smoking and alcohol at baseline and the risk of MM mortality were assessed using a Cox proportional hazards model with shared frailty. RESULTS: We observed a statistically significant dose-dependent association between BMI categories and the risk of MM mortality (<18.5 kg/m2: HR=0.80, 95% CI: 0.52-1.24; 18.5 to 24.9 kg/m2: reference; 25.0 to 29.9 kg/m2: HR=1.17, 0.94-1.47; ≥30 kg/m2: HR=1.61, 0.99-2.64, p for trend=0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes=0.150). We observed no significant associations between smoking or alcohol consumption and risk of MM mortality. CONCLUSION: This study showed that excess body mass is associated with an increased risk of MM mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of MM mortality in Asian populations. IMPACT: This study provides important evidence on the association of BMI, smoking and alcohol with the risk of MM mortality in Asian populations.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31387968

RESUMO

BACKGROUND: No epidemiological studies have directly assessed the association between dietary and urinary of isoflavonoids and risk of liver cancer in humans. METHODS: A nested case-control study including 217 incident cases of liver cancer and 427 individually matched control subjects was conducted in Shanghai, China. Dietary isoflavonoids intakes were assessed through a validated food-frequency questionnaire and the Chinese Food Composition Tables. Urinary excretion levels of four major isoflavonoids were measured by the reversed-phase high-performance liquid chromatography. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived using conditional logistic regression models. RESULTS: The adjusted ORs (95% CIs) for liver cancer across increasing quartiles of urinary genistein levels were 1.00 (reference), 0.55 (95% CI = 0.22 to 1.36), 0.57 (95% CI = 0.23 to1.43) and 0.19 (95% CI = 0.06 to 0.59) (P=0.008 for trend) in women and 1.00 (reference), 1.22(0.52,2.86), 1.17(0.47,2.90), 1.23 (0.55-2.76) in men, respectively. These associations were consistent by limiting the cases to primary malignant neoplasm of liver or malignant neoplasms of the intrahepatic bile ducts, or among participants without self-reported liver disease or cirrhosis at the baseline survey. No associations were found between dietary isoflavonoids and liver cancer risk. CONCLUSIONS: Our study suggests for the first time that urinary excretion of genistein may be associated with reduced risk of liver cancer in women. IMPACT: In this nested case-control study in China, we found that urinary excretion of genistein was associated with lower risk of liver cancer in women, and not in men.

8.
PLoS One ; 14(8): e0220864, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31425527

RESUMO

There has been marked improvement in leukemia survival, particularly among children in recent time. However, the long-term trends in survival among adult leukemia patients and the associated sex and racial survival disparities are not well understood. We, therefore, evaluated the secular trends in survival improvement of leukemia patients from 1973 through 2014, using Surveillance Epidemiology and End-Result Survey Program (SEER) data. ICD-O-3 morphology codes were used to group leukemia into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML). Survival analysis for each leukemia type stratified by race/ethnicity, age, sex was performed to generate relative survival probability estimates for the baseline time period of 1973 through 1979. Hazard ratios (HR) and respective 95% confidence intervals (CIs) for survival within subsequent 10-year time periods by race, age and sex were calculated using Cox proportional hazard models. Of the 83,255 leukemia patients for the current analysis, the 5-year survival of patients with ALL, AML, CLL, and CML during 1973-1979 were 42.0%, 6.5%, 66.5%, and 20.9%, respectively. Compared to the baseline, there were substantial improvements of leukemia-specific survival in 2010-2014 among African-American (81.0%) and Asian (80.0%) patients with CML and among 20-49 year of age with CLL (96.0%). African-American patients, those with AML and those older than 75 years of age had the lowest survival improvements. Asians experienced some of the largest survival improvements during the study period. Others, including African-American and the elderly, have not benefited as much from advances in leukemia treatment.

9.
Am J Hum Genet ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31402092

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer-colorectal, lung, ovary, prostate, pancreas, and melanoma-by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31387969

RESUMO

BACKGROUND: Regular aspirin use may lower ovarian cancer risk by blocking the cyclooxygenase enzymes, resulting in lower expression of prostaglandins, including prostaglandin E2 (PGE2). We evaluated whether higher pre-diagnosis PGE-M (a urinary biomarker of PGE2) was associated with increased ovarian cancer risk in three prospective cohorts. METHODS: We conducted a case-control study nested in the Nurses' Health Study (NHS), NHSII and Shanghai Women's Health Study (SWHS). Our analyses included 304 cases of epithelial ovarian cancer diagnosed 1996-2015 and 600 matched controls. We measured urinary PGE-M using liquid chromatography-mass spectrometry (LC/MS) with normalization to creatinine. Measures from each study were recalibrated to a common standard. We estimated odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression, with PGE-M levels modeled in quartiles. Multivariable models were adjusted for ovarian cancer risk factors. RESULTS: There was no evidence of an association between urinary PGE-M levels and ovarian cancer risk for women with PGE-M levels in the top versus bottom quartile (OR=0.80, 95%CI=0.51-1.27; p-trend=0.37). We did not observe heterogeneity by histotype (p=0.53), and there was no evidence of effect modification by BMI (p-interaction=0.82), aspirin use (p-interaction=0.59), or smoking (p-interaction=0.14). CONCLUSIONS: Pre-diagnosis urinary PGE-M levels were not significantly associated with ovarian cancer risk. Larger sample sizes are needed to consider a more modest association, and evaluate associations for specific tumor subtypes. IMPACT: Systemic prostaglandin levels do not appear strongly associated with ovarian cancer risk. Future research into aspirin use and ovarian cancer risk should consider local prostaglandins and prostaglandin-independent mechanisms.

11.
Int J Cancer ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

12.
Eur J Prev Cardiol ; : 2047487319862066, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288541

RESUMO

BACKGROUND: The recent American College of Cardiology/American Heart Association guidelines for high blood pressure lowered the hypertension criteria from systolic/diastolic blood pressure (SBP/DBP) of 140/90 mmHg or greater to 130/80 mmHg or greater, while the potential impact of the change on Chinese adults remains unclear. DESIGN: A pooled prospective cohort analysis. METHODS: Included were 154,407 Chinese adults from three prospective cohorts, which measured blood pressure at baseline and follow-up visits, and tracked death events by linkages to medical insurance system or vital statistics registries. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a total follow-up of 1,718,089 person-years, 14,692 deaths were documented including 5086 cardiovascular deaths (1277 ischaemic heart disease and 2509 cerebrovascular disease deaths). Compared to normal blood pressure (SBP/DBP < 120/80 mmHg), newly defined stage 1 hypertension (SBP/DBP 130-139/80-89 mmHg) was associated with increased cardiovascular mortality (HR 1.40, 95% CI 1.16-1.69; HR 1.36, 95% CI 1.12-1.65 for ischaemic heart disease mortality; HR 1.53, 95% CI 1.18-2.00 for cerebrovascular mortality), but not with all-cause mortality (HR 1.04, 95% CI 0.89-1.21). Stage 2 hypertension (SBP/DBP ≥ 140/90 mmHg) showed significant associations with cardiovascular disease and all-cause mortality, while elevated blood pressure (SBP 120-129 mmHg and DBP < 80 mmHg) showed null associations. The associations were stronger in adults younger than 65 years and adults without pre-existing cardiovascular disease compared with their counterparts (P for heterogeneity < 0.05). CONCLUSIONS: The newly defined stage 1 hypertension is associated with an increased risk of cardiovascular disease mortality in the Chinese population, particularly among younger adults and those without a history of cardiovascular disease.

13.
Int J Cancer ; 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351006

RESUMO

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case-cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case-control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4 ) for GNCA in NIT was 1.35 (95% CI: 0.89-2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02-2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001). In contrast, a lower risk of ESCC (NIT ESCC HR Q1:Q4 = 0.65, 95% CI: 0.45-0.92; p-trend = 0.02) was found in NIT. Low baseline ghrelin concentrations were associated with an increased risk for GNCA and GCA in the NIT and the SWHS. In contrast, low ghrelin concentrations at baseline were associated with a reduced risk of developing ESCC in the NIT. Ghrelin may be an early marker of future cancer risk for developing upper gastrointestinal cancer in regions of high incidence.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31350279

RESUMO

Smoking is an established risk factor for gastric cancer development. In this study, we aimed to assess prospectively the association of smoking with gastric cancer risk in 1,446 non-cardia gastric cancer cases and 1,796 controls from China, Japan, and Korea with consideration of H. pylori infection as a potential effect modifier. Applying logistic regression models stratified by study and adjusted for age and sex we found that current, but not former, smoking was significantly associated with gastric cancer risk (odds ratio (OR): 1.33, 95% confidence interval (CI): 1.07-1.65). However, the association was significant only in H. pylori sero-positive individuals determined by three different sero-markers: overall sero-positivity, sero-positivity to the onco-protein CagA, and sero-positivity to the gastric cancer associated sero-marker HP0305 and HP1564. Specifically, a significant interaction was found when stratifying by HP0305/HP1564 (pinteraction=0.01) with a 46% increased risk of gastric cancer among HP0305/HP1564 sero-positive current smokers (95% CI: 1.10-1.93) as opposed to no increased gastric cancer risk among HP0305/HP1564 sero-negative current smokers (OR: 0.93, 95% CI: 0.65-1.33). We confirmed that current smoking is associated with an increased gastric cancer risk, however, only among individuals that are simultaneously sero-positive for the leading causal factor for gastric cancer, H. pylori.

15.
Int J Cancer ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31265136

RESUMO

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.

16.
Int J Epidemiol ; 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31203367

RESUMO

BACKGROUND: Understanding the association between diet and colorectal cancer (CRC) risk is essential to curbing the epidemic of this cancer. This study prospectively evaluated adherence to the Chinese Food Pagoda (CHFP), and two American Dietary Guidelines: the Alternative Healthy Eating Index (AHEI-2010) and the Dietary Approaches to Stop Hypertension (DASH) in association with CRC risk among Chinese adults living in urban Shanghai, China. METHODS: Participants included 60 161 men and 72 445 women aged 40-74, from two ongoing population-based prospective cohort studies. Associations between dietary guideline compliance scores and CRC risk were evaluated by Cox proportional hazard regression analyses, with age as time metric, and potential confounders were adjusted. RESULTS: We identified 1670 CRC incidence cases (691 males and 979 females) during an average 8.1 years of follow-up for men and 13.4 years for women. CHFP score was inversely associated with risk of CRC, with hazard ratios (HRs) (95% confidence intervals) of 0.88 (0.77, 1.00), 0.86 (0.75, 0.98) and 0.84 (0.73, 0.96) for the 2nd, 3rd and 4th quartiles versus 1st quartile, respectively (Ptrend= 0.01). The inverse association appeared stronger for rectal cancer, individuals at younger age (< 50 years), with a lower BMI (<25 kg/m2) or without any metabolic conditions at baseline, although no multiplicative interactions were noted. No consistent association pattern was observed for the modified DASH score and the modified AHEI-2010. CONCLUSIONS: Compliance with the Dietary Guidelines for Chinese was associated with reduced risk of CRC among Chinese adults. To maximize health impacts, dietary recommendations need to be tailored for specific populations.

18.
Cancer Epidemiol Biomarkers Prev ; 28(8): 1308-1315, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31160347

RESUMO

BACKGROUND: Pathogenic variants in susceptibility genes lead to increased breast cancer risk. METHODS: To identify coding variants associated with breast cancer risk, we conducted whole-exome sequencing in genomic DNA samples from 831 breast cancer cases and 839 controls of Chinese women. We also genotyped samples, including 4,580 breast cancer cases and 6,695 controls, using whole exome-chip arrays. We further performed a replication study using a Multi-Ethnic Global Array in samples from 1,793 breast cases and 2,059 controls. A single marker analysis was performed using the Fisher exact test. RESULTS: We identified a missense variant (rs139379666, P2974L; AF = 0.09% for breast cancer cases, but none for controls) in the ATM gene for breast cancer risk using combing data from 7,204 breast cancer cases and 9,593 controls (P = 1.7 × 10-5). To investigate the functionality of the variant, we first silenced ATM and then transfected the overexpression vectors of ATM containing the risk alleles (TT) or reference alleles (CC) of the variant in U2OS and breast cancer SK-BR3 cells, respectively. Our results showed that compared with the reference allele, the risk allele significantly disrupts the activity of homologous recombination-mediated double-strand breaks repair efficiency. Our results further showed that the risk allele may play a defected regulation role in the activity of the ATM structure. CONCLUSIONS: Our findings identified a novel mutation that disrupts ATM function, conferring to breast cancer risk. IMPACT: Functional investigation of genetic association findings is necessary to discover a pathogenic variant for breast cancer risk.

19.
J Natl Cancer Inst ; 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31143935

RESUMO

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Utilizing a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (N=1,595). The prediction models were validated using data from the Women's Health Initiative (N=883). We applied these models to genome-wide association study (GWAS) data of 122,977 breast cancer cases and 105,974 controls to evaluate if the genetically predicted DNA methylation levels at CpGs are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62,938 CpG sites (CpGs) investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P<7.94 × 10-7, including 45 CpGs residing in 18 genomic regions which have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.

20.
Cancer Res ; 79(13): 3192-3204, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101764

RESUMO

Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.

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