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1.
Artigo em Inglês | MEDLINE | ID: mdl-33203693

RESUMO

BACKGROUND: Interleukin-27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of interleukin-27 gene has been found to increase T cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma. METHODS: Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum interleukin-27 levels and risk of developing hepatocellular carcinoma. The interleukin-27 concentrations were significantly elevated in sera collected from study participants 4-5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. RESULTS: Compared with the lowest tertile of interleukin-27, odds ratios (ORs)of hepatocellular carcinoma for the highest tertile of interleukin-27 was 46.08 [95% confidence interval (CI): 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI: 3.81-95.57) in the Shanghai Cohort Study (both ptrend <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI: 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% IC: 38.42-1529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg. CONCLUSION: Levels of interleukin-27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development. IMPACT: Interleukin-27 through its immunosuppressive property may play a significant role in the development of hepatocellular carcinoma. Serum levels of interleukin-27 may be used as a biomarker for prediction of hepatocellular carcinoma development.

2.
Hypertension ; 76(3): 750-758, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32713271

RESUMO

Systolic/diastolic blood pressure of 130 to 139/80 to 89 mm Hg has been defined as stage I hypertension by the 2017 Hypertension Clinical Practice Guidelines. Drug treatment is recommended for stage I hypertensive patients aged ≥65 years without cardiovascular disease in the 2017 Hypertension Clinical Practice Guidelines but not in the 2018 Chinese guidelines. However, the cost-effectiveness of drug treatment among this subgroup of Chinese patients is unclear. This study developed a microsimulation model to compare costs and effectiveness of drug treatment and nondrug treatment for the subgroup of stage I hypertensive patients over a lifetime horizon from a government affordability perspective. Event rates of mortality and cardiovascular complications were estimated from 3 cohorts in the Chinese population. Costs and health utilities were obtained from the national statistics report and published literature. The model predicted that drug treatment generated quality-adjusted life-years of 13.52 and associated with expected costs of $6825 in comparison with 13.81 and $7328 produced by nondrug treatment over a lifetime horizon among stage I hypertensive patients aged ≥65 years without cardiovascular disease. At a willingness-to-pay threshold of $8836/quality-adjusted life-year (the GDP per capita in 2017), drug treatment only had a 1.8% probability of being cost-effective compared with nondrug treatment after 10 000 probabilistic simulations. Sensitivity analysis of treatment costs, benefits expected from treatment, health utilities, and discount rates did not change the results. Our results suggested that drug treatment was not cost-effective compared with nondrug treatment for stage I hypertensive patients aged ≥65 years without cardiovascular disease in China.

3.
BMC Cancer ; 20(1): 576, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563240

RESUMO

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) were proposed to have potential effects against inflammation and cancer. However, results from epidemiology studies remain inconsistent. We aimed to explore the associations of plasma PUFAs with EC recurrence and all-cause mortality. METHOD: Women diagnosed with endometrial cancer (EC) between 2008 and 2013 and underwent surgery at Fudan University Shanghai Cancer Center of China were recruited. Survival status was followed up through September 2017. EC recurrence and total cause deaths were identified through medical record and telephone interview. In total, 202 patients with enough plasma samples at time of surgery were included. There were 195 patients who provided baseline plasma and survival information included in the current study. Plasma omega-3 PUFAs were measured by GC-FID. Cox Proportional Hazard model adjusted for potential cofounders was used to estimate HRs and 95% CIs. RESULTS: Median follow-up time for patients was 58 months after surgery. A total of 13 recurrences and 11 all-cause deaths, of which, 2 deaths from EC, were identified. Level of plasma EPA was higher in recurrent patients than total patients (0.78% vs 0.51%, P = 0.015). Higher plasma eicosapentaenoic acid (EPA) level trended to have positive association with EC recurrence (P-trend = 0.04), although comparing to the lowest tertile, the highest tertile of EPA level was not significantly associated with increased risk of EC recurrence (HRT3vsT1 = 6.02; 95%CI = 0.7-52.06). The association between total omega-3 PUFA and EC recurrence tended to be stronger among patients with deeper myometrial invasion (OR = 3.41; 95%CI = 1.06-10.95; P-interaction = 0.04). CONCLUSIONS: Higher plasma EPA level was significantly associated with EC recurrence. Further studies are warranted to confirm these findings. TRIAL REGISTRATION: ChiCTR1900025418; Retrospectively registered (26 August 2019); Chinses Clinical Trial Registry.

4.
Tob Control ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546664

RESUMO

BACKGROUND: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts. METHODS: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis. FINDINGS: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence. CONCLUSIONS: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice.

5.
Nat Commun ; 11(1): 1217, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139696

RESUMO

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Predisposição Genética para Doença , Feminino , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Receptores Estrogênicos/metabolismo , Fatores de Risco
6.
Int J Cancer ; 147(7): 1917-1927, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32222976

RESUMO

Deficiencies in methyl donor status may render DNA methylation changes and DNA damage, leading to carcinogenesis. Epidemiological studies reported that higher dietary intake of choline is associated with lower risk of pancreatic cancer, but no study has examined the association of serum choline and its metabolites with risk of pancreatic cancer. Two parallel case-control studies, one nested within the Shanghai Cohort Study (129 cases and 258 controls) and the other within the Singapore Chinese Health Study (58 cases and 104 controls), were conducted to evaluate the associations of baseline serum concentrations of choline, betaine, methionine, total methyl donors (i.e., sum of choline, betaine and methionine), dimethylglycine and trimethylamine N-oxide (TMAO) with pancreatic cancer risk. In the Shanghai cohort, odds ratios and 95% confidence intervals of pancreatic cancer for the highest quartile of choline, betaine, methionine, total methyl donors and TMAO were 0.27 (0.11-0.69), 0.57 (0.31-1.05), 0.50 (0.26-0.96), 0.37 (0.19-0.73) and 2.81 (1.37-5.76), respectively, compared to the lowest quartile. The corresponding figures in the Singapore cohort were 0.85 (0.23-3.17), 0.50 (0.17-1.45), 0.17 (0.04-0.68), 0.33 (0.10-1.16) and 1.42 (0.50-4.04). The inverse associations of methionine and total methyl donors including choline, betaine and methionine with pancreatic cancer risk in both cohorts support that DNA repair and methylation play an important role against the development of pancreatic cancer. In the Shanghai cohort, TMAO, a gut microbiota-derived metabolite of dietary phosphatidylcholine, may contribute to higher risk of pancreatic cancer, suggesting a modifying role of gut microbiota in the dietary choline-pancreatic cancer risk association.

8.
Am J Clin Nutr ; 111(3): 644-656, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915809

RESUMO

BACKGROUND: Choline-related nutrients are dietary precursors of a gut microbial metabolite, trimethylamine-N-oxide, which has been linked to cardiometabolic diseases and related death. However, epidemiologic evidence on dietary choline and mortality remains limited, particularly among nonwhite populations. OBJECTIVES: This study aimed to investigate the associations of choline-related nutrients with cardiometabolic and all-cause mortality among black and white Americans and Chinese adults. METHODS: Included were 49,858 blacks, 23,766 whites, and 134,001 Chinese, aged 40-79 y, who participated in 3 prospective cohorts and lived ≥1 y after enrollment. Cox regression models were used to estimate HRs and 95% CIs for cardiometabolic [e.g., ischemic heart disease (IHD), stroke, and diabetes] and all-cause deaths. To account for multiple testing, P values < 0.003 were considered significant. RESULTS: Mean choline intake among blacks, whites, and Chinese was 404.1 mg/d, 362.0 mg/d, and 296.8 mg/d, respectively. During a median follow-up of 11.7 y, 28,673 deaths were identified, including 11,141 cardiometabolic deaths. After comprehensive adjustments, including for overall diet quality and disease history, total choline intake was associated with increased cardiometabolic mortality among blacks and Chinese (HR for highest compared with lowest quintile: 1.26; 95% CI: 1.13, 1.40 and HR: 1.23; 95% CI: 1.11, 1.38, respectively; both P-trend < 0.001); among whites, the association was weaker (HR: 1.12; 95% CI: 0.95, 1.33; P-trend = 0.02). Total choline intake was also associated with diabetes and all-cause mortality in blacks (HR: 1.66; 95% CI: 1.26, 2.19 and HR: 1.20; 95% CI: 1.12, 1.29, respectively), with diabetes mortality in Chinese (HR: 2.24; 95% CI: 1.68, 2.97), and with IHD mortality in whites (HR: 1.31; 95% CI: 1.02, 1.69) (all P-trend < 0.001). The choline-mortality association was modified by alcohol consumption and appeared stronger among individuals with existing cardiometabolic disease. Betaine intake was associated with increased cardiometabolic mortality in Chinese only (HR: 1.16; 95% CI: 1.08, 1.25; P-trend < 0.001). CONCLUSIONS: High choline intake was associated with increased cardiometabolic mortality in racially diverse populations.


Assuntos
Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/mortalidade , Colina/metabolismo , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Grupo com Ancestrais do Continente Asiático , Doenças Cardiovasculares/metabolismo , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Nutr Metab Cardiovasc Dis ; 30(3): 467-473, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-31831367

RESUMO

BACKGROUND AND AIMS: Studies have linked several metabolites to the risk of coronary heart disease (CHD) among Western populations, but prospective studies among Asian populations on the metabolite-CHD association remain limited. METHODS AND RESULTS: We evaluated the association of urinary metabolites with CHD risk among Chinese adults in a nested case-control study of 275 incident cases and 275 matched controls (127 pairs of men and 148 pairs of women). Fifty metabolites were measured by a predefined metabolomics panel and adjusted using urinary creatinine. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). After adjusting for traditional CHD risk factors, urinary tryptophan showed a positive association with incident CHD: OR (95% CI) for the highest vs. lowest quartiles was 2.02 (1.15-3.56) among all study participants (p-trend = 0.02). The tryptophan-CHD association was more evident among individuals with dyslipidemia than among those without the condition (OR [95% CI] for the highest vs. lowest quartiles = 3.90 [1.86-8.19] and 0.74 [0.26-2.06], respectively; p-interaction<0.01). Other metabolites did not show significant associations with CHD risk among all study participants. However, a positive association of methionine with CHD risk was observed only among women (OR [95% CI] for the highest vs. lowest quartiles = 2.77 [1.17-6.58]; p-interaction = 0.03), and an inverse association of inosine with CHD risk was observed only among men (OR [95% CI] for the highest vs. lowest quartiles = 0.29 [0.11-0.81]; p-interaction = 0.04). CONCLUSION: Elevated urinary tryptophan may be related to CHD risk among Chinese adults, especially for those with dyslipidemia.

10.
Int J Cancer ; 146(10): 2728-2735, 2020 May 15.
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.

11.
Int J Cancer ; 146(9): 2394-2405, 2020 May 01.
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 ; 27(4): 345-354, 2020 Mar.
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 Epidemiol ; 49(1): 56-68, 2020 02 01.
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.

14.
Hepatology ; 71(3): 917-928, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31318976

RESUMO

BACKGROUND AND AIMS: Exposure to metals may promote the risk for cancers. We evaluated the associations of a broad spectrum of metals with gallbladder cancer (GBC) and gallstones. APPROACH AND RESULTS: A total of 259 patients with GBC, 701 patients with gallstones, and 851 population-based controls were enrolled in Shanghai, China. A metallome panel was used to simultaneously detect 18 metals in serum through inductively coupled plasma-mass spectrometry. Logistic regression models were used to estimate crude or adjusted odds ratios (ORadj ) with 95% confidence intervals (CIs) for the association between metal levels and gallbladder disease. Among the 18 metals tested, 12 were significantly associated with GBC and six with gallstones (Pcorrected  < 0.002). Boron, lithium, molybdenum, and arsenic levels were associated with GBC compared to gallstones as well as with gallstones compared to population-based controls. Elevated levels of cadmium, chromium, copper, molybdenum, and vanadium were positively associated with GBC versus gallstones; and the ORadj for the highest tertile (T3) compared to the lowest tertile (T1) ranged from 1.80 to 7.28, with evidence of dose-response trends (P < 0.05). Arsenic, boron, iron, lithium, magnesium, selenium, and sulfur were inversely associated with GBC, with the T3 versus T1 ORadj ranging from 0.20 to 0.69. Arsenic, boron, calcium, lithium, molybdenum, and phosphorus were negatively associated with gallstones, with the T3 versus T1 ORadj ranging from 0.50 to 0.75 (P < 0.05). CONCLUSIONS: Metals were associated with both GBC and gallstones, providing cross-sectional evidence of association across the natural history of disease. Longitudinal studies are needed to evaluate the temporality of metal exposure and gallbladder diseases and to investigate the mechanisms of disease pathogenesis.

15.
Cancer Epidemiol Biomarkers Prev ; 29(2): 477-486, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31826910

RESUMO

BACKGROUND: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10-8; rs62558833, P = 7.5 × 10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

16.
Int J Cancer ; 146(8): 2175-2181, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837001

RESUMO

The missing heritability of breast cancer could be partially attributed to rare variants (MAF < 0.5%). To identify breast cancer-associated rare coding variants, we conducted whole-exome sequencing (~50×) in genomic DNA samples obtained from 831 breast cancer cases and 839 controls of Chinese females. Using burden tests for each gene that included rare missense or predicted deleterious variants, we identified 29 genes showing promising associations with breast cancer risk. We replicated the association for two genes, OGDHL and BRCA2, at a Bonferroni-corrected p < 0.05, by genotyping an independent set of samples from 1,628 breast cancer cases and 1,943 controls. The association for OGDHL was primarily driven by three predicted deleterious variants (p.Val827Met, p.Pro839Leu, p.Phe836Ser; p < 0.01 for all). For BRCA2, we characterized a total of 27 disruptive variants, including 18 nonsense, six frameshift and three splicing variants, whereas they were only detected in cases, but none of the controls. All of these variants were either very rare (AF < 0.1%) or not detected in >4,500 East Asian women from the genome Aggregation database (gnomAD), providing additional support to our findings. Our study revealed a potential novel gene and multiple disruptive variants of BRCA2 for breast cancer risk, which may identify high-risk women in Chinese populations.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Complexo Cetoglutarato Desidrogenase/genética , Adulto , Idoso , Estudos de Casos e Controles , China , Bases de Dados Genéticas , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma
17.
Cancer Epidemiol Biomarkers Prev ; 29(1): 127-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31685561

RESUMO

BACKGROUND: Cotinine is a metabolite of nicotine. Serum and urinary cotinine are validated biomarkers for cigarette exposure. Their performance for lung cancer risk prediction has not been simultaneously examined in epidemiologic studies. METHODS: A nested case-control study, including 452 incident lung cancer cases and 452 smoking-matched controls in the Shanghai cohort study, was conducted. Mass spectrometry-based methods were used to quantify cotinine in serum and urine samples collected from current smokers at baseline, on average 10 years before cancer diagnosis of cases. Logistic regression was used to estimate ORs, 95% confidence intervals (CI), and AUC ROC for lung cancer associated with higher levels of cotinine. RESULTS: Serum and urinary cotinine levels were significantly higher in lung cancer cases than controls. Compared with the lowest quartile serum cotinine (≤0.40 nmol/mL), the OR of lung cancer for smokers in the highest quartiles (>1.39 nmol/mL) was 5.46 (95% CI, 3.38-8.81). Similarly, the OR was 5.49 (95% CI, 3.39-8.87) for highest (>16.38 nmol/mg creatinine) relative to the lowest quartile of urinary total cotinine (≤4.11 nmol/mg creatinine). A risk prediction model yielded an AUC of 0.72 (95% CI, 0.69-0.75) for serum cotinine and 0.72 (95% CI, 0.69-0.75) for urinary total cotinine combined with smoking history. CONCLUSIONS: Urinary and serum cotinine have the same performance in prediction of lung cancer risk for current smokers. IMPACT: Urinary cotinine is a noninvasive biomarker that can replace serum cotinine in risk prediction of future lung cancer risk for current smokers.

18.
Int J Cancer ; 146(3): 839-849, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31001807

RESUMO

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and ß-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher ß-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; ptrend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; ptrend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between ß-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.


Assuntos
Poluentes Ambientais/sangue , Hidrocarbonetos Clorados/sangue , Linfoma não Hodgkin/epidemiologia , Praguicidas/sangue , Idoso , Estudos de Casos e Controles , China/epidemiologia , Poluentes Ambientais/efeitos adversos , Feminino , Seguimentos , Humanos , Hidrocarbonetos Clorados/efeitos adversos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/etiologia , Masculino , Pessoa de Meia-Idade , Praguicidas/efeitos adversos , Estudos Prospectivos , Fatores de Risco , Singapura/epidemiologia
19.
JAMA Netw Open ; 2(12): e1917371, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31834393

RESUMO

Importance: The association of weight gain from early to middle adulthood with disease risk has not been adequately studied. Objective: To investigate the association of adult weight gain with major health outcomes in a Chinese population with low body weight in early adulthood. Design, Setting, and Participants: This population-based cohort study assessed data from 48 377 women and 35 989 men aged 40 to 59 years at recruitment in 2 prospective cohort studies in China. The Shanghai Women's Health Study recruited 74 941 women, aged 40 to 70 years, from January 1, 1996, to December 31, 2000, and the Shanghai Men's Health Study recruited 61 482 men, aged 40 to 74 years, from January 1, 2002, to December 31, 2006. This analysis was conducted from September 1, 2017, to April 30, 2018. Exposures: Weight gain from 20 years of age to 40 to 59 years of age. Main Outcomes and Measures: Mortality and incidence of cancers and other chronic diseases. Results: This analysis included 48 377 women (mean [SD] age, 47.8 [5.3] years) and 35 989 men (mean [SD] age, 49.6 [5.1] years). Per 5-kg weight gain from early to middle adulthood was associated with an approximately 10% (hazard ratio [HR], 1.09; 95% CI, 1.04-1.14 for men; HR, 1.14; 95% CI, 1.11-1.19 for women) elevated all-cause mortality and a greater than 20% (HR, 1.26; 95% CI, 1.16-1.38 for men; HR, 1.23; 95% CI, 1.14-1.33 for women) cardiovascular disease-related mortality in later life among individuals who reached a body mass index (BMI) of 23 or higher at middle adulthood. Body mass index at middle adulthood also modified the association of weight gain with risk of obesity-related cancers, with weight gain of 20 kg or more associated with increased risks both for men (HR, 1.34; 95% CI, 1.07-1.67) and for women (HR 1.45; 95% CI, 1.24-1.68). No similar associations were found for individuals with a BMI of 18.5 to 22.9. Regardless of BMI, weight gain was associated with elevated risks of type 2 diabetes, hypertension, fatty liver disease, stroke, gout, and gallstones, particularly for type 2 diabetes (HR, 7.87; 95% CI, 6.91-8.97 for women; HR, 4.95; 95% CI, 4.23-5.79 for men) and fatty liver disease (HR, 3.68; 95% CI, 3.42-3.95 for women; HR, 2.83, 95% CI, 2.56-3.13 for men) in individuals with weight gain of 20 kg or more compared with those with a healthy weight. Conclusions and Relevance: This study found that weight gain from early to middle adulthood was associated with disease incidence and mortality in later life. The BMI at middle adulthood modified the association of weight gain with mortality and cancer incidence but not risk of other major chronic diseases.

20.
JAMA Oncol ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31647500

RESUMO

Importance: Dietary fiber (the main source of prebiotics) and yogurt (a probiotic food) confer various health benefits via modulating the gut microbiota and metabolic pathways. However, their associations with lung cancer risk have not been well investigated. Objective: To evaluate the individual and joint associations of dietary fiber and yogurt consumption with lung cancer risk and to assess the potential effect modification of the associations by lifestyle and other dietary factors. Design, Setting, and Participants: This pooled analysis included 10 prospective cohorts involving 1 445 850 adults from studies that were conducted in the United States, Europe, and Asia. Data analyses were performed between November 2017 and February 2019. Using harmonized individual participant data, hazard ratios and 95% confidence intervals for lung cancer risk associated with dietary fiber and yogurt intakes were estimated for each cohort by Cox regression and pooled using random-effects meta-analysis. Participants who had a history of cancer at enrollment or developed any cancer, died, or were lost to follow-up within 2 years after enrollment were excluded. Exposures: Dietary fiber intake and yogurt consumption measured by validated instruments. Main Outcomes and Measures: Incident lung cancer, subclassified by histologic type (eg, adenocarcinoma, squamous cell carcinoma, and small cell carcinoma). Results: The analytic sample included 627 988 men, with a mean (SD) age of 57.9 (9.0) years, and 817 862 women, with a mean (SD) age of 54.8 (9.7) years. During a median follow-up of 8.6 years, 18 822 incident lung cancer cases were documented. Both fiber and yogurt intakes were inversely associated with lung cancer risk after adjustment for status and pack-years of smoking and other lung cancer risk factors: hazard ratio, 0.83 (95% CI, 0.76-0.91) for the highest vs lowest quintile of fiber intake; and hazard ratio, 0.81 (95% CI, 0.76-0.87) for high vs no yogurt consumption. The fiber or yogurt associations with lung cancer were significant in never smokers and were consistently observed across sex, race/ethnicity, and tumor histologic type. When considered jointly, high yogurt consumption with the highest quintile of fiber intake showed more than 30% reduced risk of lung cancer than nonyogurt consumption with the lowest quintile of fiber intake (hazard ratio, 0.67 [95% CI, 0.61-0.73] in total study populations; hazard ratio 0.69 [95% CI, 0.54-0.89] in never smokers), suggesting potential synergism. Conclusions and Relevance: Dietary fiber and yogurt consumption was associated with reduced risk of lung cancer after adjusting for known risk factors and among never smokers. Our findings suggest a potential protective role of prebiotics and probiotics against lung carcinogenesis.

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