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1.  Vitamin Intake and Liver Cancer Risk: A Report From Two Cohort Studies in China 
Correspondence to: Xiao-Ou Shu, MD, PhD, Vanderbilt Epidemiology Center, 2525 West End Ave, Ste 600 (IMPH), Nashville, TN 37203-1738 (e-mail: xiao-ou.shu@vanderbilt.edu) and Yong-Bing Xiang, MD, MSc, Shanghai Cancer Institute, No. 25, Lane 2200, Xie Tu Road, Shanghai 200032, People’s Republic of China (e-mail: ybxiang@shsci.org).Background
Epidemiologic studies on the relationship between vitamin intake and liver cancer risk are sparse and inconsistent.
Methods
We evaluated vitamin intake from diet and supplements and risk of liver cancer in 132 837 women and men from China who were recruited into the Shanghai Women’s Health Study from 1997 to 2000 or the Shanghai Men’s Health Study from 2002 to 2006. In-person interviews, using a validated food-frequency questionnaire, were conducted to collect data on dietary habits. Follow-up consisted of in-person surveys and record linkage. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazard models with adjustment for potential confounders to compare liver cancer risk among participants with high vs low vitamin intake. All statistical tests were two-sided.
Results
After excluding the first 2 years of follow-up, 267 participants (including 118 women and 149 men) developed liver cancer during an average of 10.9 (Shanghai Women’s Health Study) or 5.5 (Shanghai Men’s Health Study) years of follow-up. Dietary vitamin E intake was inversely associated with liver cancer risk (P trend = .01), as was vitamin E supplement use (hazard ratio = 0.52, 95% confidence interval = 0.30 to 0.90). This association was consistent among participants with and without self-reported liver disease or a family history of liver cancer. Vitamin C and multivitamin use was associated with increased risk among participants with self-reported liver disease or family history of liver cancer, whereas intake of vitamin C and other vitamins from dietary sources was unrelated to liver cancer risk.
Conclusions
Vitamin E intake, either from diet or supplements, may reduce the risk of liver cancer.
doi:10.1093/jnci/djs277
PMCID: PMC3611811  PMID: 22811438
2.  Cruciferous vegetables, glutathione S-transferase polymorphisms and the risk of colorectal cancer among Chinese men 
Annals of epidemiology  2013;24(1):10.1016/j.annepidem.2013.10.003.
Purpose
To assess the associations between cruciferous vegetable (CV) intake, GST gene polymorphisms and colorectal cancer (CRC) in a population of Chinese men.
Methods
Using incidence density sampling, CRC cases (N = 340) diagnosed prior to December 31, 2010 within the Shanghai Men’s Health Study were matched to non-cases (N = 673). CV intake was assessed from a food frequency questionnaire and by isothiocyanate (ITC) levels from spot urine samples. GSTM1 and GSTT1 were categorized as null (0 copies) versus non-null (1 or 2 copies). Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between CV intake and GST gene variants with CRC and statistical interactions were evaluated.
Results
CRC risk was not associated with CV intake, whether measured by self-report or by urinary ITC, nor with GST gene variants. No statistical interactions were detected between CV intake and GST gene variants on the odds of CRC. Stratifying by timing of urine sample collection and excluding CRC cases diagnosed in the first two years did not materially alter the results.
Conclusions
This study provides no evidence supporting the involvement of CV intake in the development of CRC in Chinese men.
doi:10.1016/j.annepidem.2013.10.003
PMCID: PMC3864981  PMID: 24238877
brassicaceae; China; colorectal neoplasms; glutathione S-transferase M1; glutathione S-transferase T1; men
3.  Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men 
Cancer epidemiology  2013;37(6):10.1016/j.canep.2013.08.003.
Purpose
Translesion DNA synthesis (TLS) plays an important role in promoting replication through DNA lesions. Genetic polymorphisms in TLS genes may have potential roles in lung cancer development in humans.
Methods
We evaluated the association between genetic variants in six TLS genes and the risk and survival of lung cancer in a case-control study in China. Included in the study are 224 lung cancer patients and 448 healthy controls.
Results
Carriers of the CG genotype of POLκ rs5744724 had significantly reduced risk of lung cancer (odds ratio (OR) = 0.60, 95% confidence interval (CI): 0.42-0.87), comparing with those carrying the CC genotype, and the AA genotype of PCNA rs25406 was also associated with significantly decreased cancer risk compared with the major homozygote alleles (OR= 0.47, 95% CI: 0.25-0.86). Haplotype analysis showed that subjects with the POLκ C-G (rs5744533-rs5744724) haplotype had decreased risk of lung cancer (OR = 0.69, 95% CI: 0.49-0.98), comparing with those carrying the C-C haplotype. Besides, the heterozygotes of REV1 rs3087386 and rs3792136 were independent prognostic factors for lung cancer survival with hazard ratios (HR) 1.54 (95% CI: 1.12-2.12) and 1.44 (95% CI: 1.06-1.97) respectively.
Conclusions
Our findings suggested that genetic variants in POLκ and PCNA genes may play roles in the susceptibility of lung cancer, and REV1 gene may have roles in lung cancer survival in Chinese men.
doi:10.1016/j.canep.2013.08.003
PMCID: PMC3875838  PMID: 24012694
lung cancer; TLS pathway; genetic mutation; susceptibility; survival; men
4.  Vegetable-based dietary pattern and liver cancer risk: results from the Shanghai Women's and Men's Health Studies 
Cancer science  2013;104(10):1353-1361.
Summary
Although dietary patterns, specific foods, and their constituents have been linked to cancer risk, the role of dietary patterns and specific food groups in liver cancer risk has not been investigated. In the Shanghai Women's Health Study (SWHS) and Shanghai Men's Health Study (SMHS), two cohort studies of 132 837 Chinese women and men, we evaluated the relationship between dietary patterns, food groups, and liver cancer risk. Through in-person interviews, dietary information intake over the preceding year was collected by using a validated food-frequency questionnaire. Cox regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. During an average follow-up of 10.9 (SWHS) or 5.5 (SMHS) years, 267 incident liver cancer cases were identified after the first 2 years of study enrollment. Three dietary patterns were derived by factor analysis. A vegetable-based dietary pattern was inversely associated with liver cancer; HRs (95% CIs) for the lowest to highest quartiles were: 1.00, 0.98 (0.71–1.35), 0.93 (0.67–1.29), and 0.58 (0.40–0.84); Ptrend=0.01). The association was stronger among participants with a history of chronic liver disease. Further analyses showed high intakes of celery, mushrooms, allium vegetables, composite vegetables (including asparagus lettuce and garland chrysanthemum), legumes, and legume products were associated with reduced liver cancer risk (all Ptrend<0.05). Fruit- and meat-based dietary patterns were not associated with liver cancer risk. Our study suggests that a vegetable-based dietary pattern is associated with reduced liver cancer risk.
doi:10.1111/cas.12231
PMCID: PMC3879410  PMID: 23841909
Liver cancer; dietary patterns; food groups; vegetables; prospective study
5.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Purpose
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Results
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
Conclusion
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
doi:10.1200/JCO.2012.48.2596
PMCID: PMC3699726  PMID: 23733771
6.  Pre-existing type 2 diabetes and risk of lung cancer: a report from two prospective cohort studies of 133 024 Chinese adults in urban Shanghai 
BMJ Open  2014;4(7):e004875.
Objectives
Observational studies of type 2 diabetes (T2D) and lung cancer risk are limited and controversial. We thus examined the association between T2D and risk of incident lung cancer using a cohort design.
Setting
Data from two ongoing population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002–2006 and the Shanghai Women's Health Study, SWHS, 1996–2000) were used. Cox proportional-hazards regression models with T2D as a time-varying exposure were modelled to estimate HRs and 95% CIs.
Participants
The study population included 61 491 male participants aged 40–74 years from SMHS and 74 941 female participants aged 40–70 years from SWHS.
Outcome measure
Lung cancer cases were identified through annual record linkage to the Shanghai Cancer Registry and Shanghai Municipal Registry of Vital Statistics, and were further verified through home visits and a review of medical charts by clinical and/or pathological experts. Outcome data until 31 December 2010 for men and women were used for the present analysis.
Results
After a median follow-up of 6.3 years for SMHS and 12.2 years for SWHS, incident lung cancer cases were detected in 492 men and 525 women. A null association between T2D and lung cancer risk was observed in men (HR=0.87, 95% CI 0.62 to 1.21) and women (HR=0.92, 95% CI 0.69 to 1.24) after adjustments for potential confounders. Similar results were observed among never smokers.
Conclusions
There is little evidence that pre-existing T2D may influence the incidence of lung cancer.
doi:10.1136/bmjopen-2014-004875
PMCID: PMC4091264  PMID: 24993754
EPIDEMIOLOGY; ONCOLOGY; PUBLIC HEALTH
7.  Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women 
Journal of Clinical Oncology  2013;31(12):1548-1553.
Purpose
We recently reported an inverse association between soy food intake and lung cancer risk among nonsmoking women. The effect size for aggressive lung cancers was larger than that observed for other types of lung cancer. Therefore, we hypothesized that soy consumption may favorably affect the overall survival of patients with lung cancer.
Patients and Methods
This analysis included 444 women with incident lung cancer identified from the Shanghai Women's Health Study. Prediagnosis soy food intake was assessed at enrollment and reassessed 2 years later. Proportional hazards models were used to evaluate the association between soy food intake and overall survival.
Results
Of the 444 patients with lung cancer, 318 died during follow-up. Initial analyses including all patients showed that higher intake of soy food was associated with better overall survival after adjusting for demographic and lifestyle characteristics and other nonclinical factors. Larger effect sizes for the association were found after additional adjustment for tumor stage and treatment in analyses including 301 patients with data available on these clinical factors. Compared with the median intake of soy food, fully adjusted hazard ratios for total mortality associated with the 10th, 30th, 70th, and 90th percentiles of intake were 1.81 (95% CI, 1.26 to 2.59), 1.25 (95% CI, 1.09 to 1.42), 0.88 (95% CI, 0.80 to 0.97), and 0.89 (95% CI, 0.68 to 1.16), respectively. Similar inverse associations were observed for dietary isoflavone intake.
Conclusion
This study suggests, to the best of our knowledge for the first time, that, among women with lung cancer, prediagnosis intake of soy food is associated with better overall survival.
doi:10.1200/JCO.2012.43.0942
PMCID: PMC3625711  PMID: 23530109
8.  A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2 
Human Molecular Genetics  2013;23(4):1108-1119.
Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
doi:10.1093/hmg/ddt488
PMCID: PMC3900106  PMID: 24105470
9.  Vitamin E intake and the lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study 
Vitamin E includes several tocopherol isoforms which may reduce lung cancer risk, but past studies evaluating the association between vitamin E intake and lung cancer risk were inconsistent. We prospectively investigated the associations between tocopherol intake from diet and from supplements with lung cancer risk among 72,829 Chinese female nonsmokers aged 40-70 years and participating in the Shanghai Women’s Health Study (SWHS). Dietary and supplement tocopherol exposure was assessed by a validated food-frequency questionnaire at baseline, and also reassessed for change in intake during follow-up. Cox proportional hazards models with time-dependent covariates were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence interval (CIs) for lung cancer. After 12.02 years of follow-up, 481 women were diagnosed with lung cancer. Total dietary tocopherol was inversely associated with lung cancer risk among women meeting dietary guidelines for adequate intake (AI) of tocopherol (14 mg/day or more: HR: 0.78; 95% CI 0.60-0.99; compared to the category less than AI). The protective association between dietary tocopherol intake and lung cancer was restricted to women exposed to side-stream smoke in the home and workplace (HR=0.53 (0.29-0.97), p-trend = 0.04). In contrast, vitamin E supplement use was associated with increased lung cancer risk (HR: 1.33; 95% CI 1.01-1.73), more so for lung adenocarcinoma risk (HR: 1.79; 95% CI 1.23-2.60). In summary, dietary tocopherol intake may reduce the risk of lung cancer among female non-smokers, however supplements may increase lung adenocarcinoma risk and requires further investigation.
doi:10.1002/ijc.29016
PMCID: PMC4232456  PMID: 24916784
diet; dietary supplements; lung neoplasm; prospective study; tocopherols; women
10.  Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1 
Nature genetics  2014;46(8):886-890.
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
doi:10.1038/ng.3041
PMCID: PMC4127632  PMID: 25038754
11.  Dietary Iron Intake and Risk of Endometrial Cancer: A Population-based Case-Control Study in Shanghai, China 
Nutrition and cancer  2010;62(1):40-50.
Dietary red meat and animal fat have been linked to endometrial cancer (EC) risk, but the impact of bioavailable iron in animal-derived foods has been less well studied. Our objective was to investigate the effects of iron and fats on the risk of EC in a large, population-based, case-control study. The Shanghai Endometrial Cancer Study enrolled 1,204 EC cases and 1,212 controls who completed in-person interviews, including a food frequency questionnaire. Animal-derived iron and fat intakes were calculated from dietary intakes and food composition tables. Logistic regression models were used to evaluate independent and joint effects of iron and fat on EC risk. Animal-derived iron intake was positively associated with EC risk [adjusted OR = 1.9; 95% CI = 1.4–2.7, Ptrend < 0.01, highest vs. lowest quartile], predominantly after menopause (OR = 2.2; 95%CI = 1.4–3.4, Ptrend < 0.01) and in women with BMI ≥ 25 kg/m2(OR = 3.2; 95% CI = 1.4–7.5 in postmenopausal obese women, Ptrend < 0.01). Animal-derived fat was also associated with postmenopausal EC risk (OR = 1.7; 95% CI = 1.2–2.5, Ptrend < 0.01). Multiplicative interactions between animal-derived iron and BMI or animal-derived fat intake were not observed. Animal-derived iron intake is associated with increased risk of EC after menopause and among obese women. Avoidance of animal-derived (heme) iron may reduce the risk of EC in these women.
doi:10.1080/01635580903191544
PMCID: PMC4310680  PMID: 20043258
12.  Circulating cytokines and gastric cancer risk 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0284-z.
Purpose:
Chronic inflammation has been hypothesized to play a significant role in the etiology of cancer, including gastric cancer. In the present study we sought to examine pre-diagnostic systemic cytokine levels in plasma, which can be seen as markers of aggregate inflammation, and risk of distal gastric cancer in a case-control study nested within the prospective Shanghai Men’s Health Study.
Methods:
Circulating levels of eight inflammation-related cytokines were measured in the plasma collected at baseline for 180 incident cases of distal gastric cancer and 358 matched controls. Helicobacter pylori sero-positivity was assessed using multiplex serology. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals.
Results:
Individuals with IL-8 levels above the lowest quartile were at two-fold increased odds of gastric cancer [OR 1.91 (95% CI 1.05-3.46), OR 2.10 (95% CI 1.19-3.74), and OR 2.30 (95% CI 1.26-4.19), for the second through fourth quartiles, respectively]. While there were suggestions of an increase in risk with increased level of many of the other cytokines measured (IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ), no significant associations were found at the p<0.05 level. Infection with CagA-positive H. pylori did not modify these associations.
Conclusions:
In a population with high gastric cancer incidence and high H. pylori prevalence, increased circulating levels of IL-8 may indicate increased risk of gastric cancer. These findings add to our understanding of the disease, and further efforts to uncover biomarkers of disease risk.
doi:10.1007/s10552-013-0284-z
PMCID: PMC3828746  PMID: 24052422
inflammation; cytokines; gastric cancer; epidemiology
13.  Circulating C-reactive protein and colorectal cancer risk: a report from the Shanghai Men’s Health Study 
Carcinogenesis  2013;34(12):2799-2803.
Chronic inflammation has been implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the association of prediagnostic circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation, with subsequent development of colorectal cancer. Prediagnostic plasma CRP levels were examined among 288 colorectal cancer cases and 576 individually-matched controls nested within the Shanghai Men’s Health Study (2002–06), a population-based cohort study of 61 482 Chinese men. The association between CRP levels and colorectal cancer risk was investigated. Baseline plasma CRP levels were 53% higher among men who subsequently developed colorectal cancer than among those who remained free of the disease (1.15 versus 0.75 μg/ml; P < 0.001). Multivariate analyses showed a dose-dependent relationship between CRP and colorectal cancer risk (P trend = 0.003); men in the highest tertile (CRP > 1.19 μg/ml) had 1.88-fold (95% confidence interval (CI): 1.24–2.86) increased odds of developing colorectal cancer compared with men in the lowest tertile (CRP < 0.45 μg/ml). The association was only significant for colon cancer, when cancer site was considered, and was predominantly seen for cases diagnosed within 4 years of blood collection; adjusted odds ratios for the highest versus the lowest tertiles were 3.28 (95% CI: 1.28–8.37), 3.68 (95% CI: 1.62–8.38) and 1.05 (95% CI: 0.56–1.97), respectively, for cases diagnosed <2, 2–4 and >4 years after blood collection. The findings from our study suggest that circulating CRP level is positively associated with colorectal cancer risk in Chinese men, and this association, at least in part, is explained by inflammation-related cancerous or precancerous processes.
doi:10.1093/carcin/bgt288
PMCID: PMC3845894  PMID: 23985781
14.  Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk 
Nature genetics  2014;46(6):533-542.
Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10−8 to 9.22 × 10−21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways.
doi:10.1038/ng.2985
PMCID: PMC4068797  PMID: 24836286
15.  Dietary Carbohydrates, Refined Grains, Glycemic Load, and Risk of Coronary Heart Disease in Chinese Adults 
American Journal of Epidemiology  2013;178(10):1542-1549.
The potential long-term association between carbohydrate intake and the risk of coronary heart disease (CHD) remains unclear, especially among populations who habitually have high-carbohydrate diets. We prospectively examined intakes of carbohydrates and staple grains as well as glycemic index and glycemic load in relation to CHD among 117,366 Chinese women and men (40–74 years of age) without history of diabetes, CHD, stroke, or cancer at baseline in Shanghai, China. Diet was assessed using validated food frequency questionnaires. Incident CHD cases were ascertained during follow-ups (in women, the mean was 9.8 years and in men, the mean was 5.4 years) and confirmed by medical records. Carbohydrate intake accounted for 67.5% of the total energy intake in women and 68.5% in men. Seventy percent of total carbohydrates came from white rice and 17% were from refined wheat products. Positive associations between carbohydrate intakess and CHD were found in both sexes (all P for heterogeneity > 0.35). The combined multivariate-adjusted hazard ratios for the lowest to highest quartiles of carbohydrate intake, respectively, were 1.00, 1.38, 2.03, and 2.88 (95% confidence interval: 1.44, 5.78; P for trend = 0.001). The combined hazard ratios comparing the highest quartile with the lowest were 1.80 (95% confidence interval: 1.01, 3.17) for refined grains and 1.87 (95% confidence interval: 1.00, 3.53) for glycemic load (both P for trend = 0.03). High carbohydrate intake, mainly from refined grains, is associated with increased CHD risk in Chinese adults.
doi:10.1093/aje/kwt178
PMCID: PMC3888273  PMID: 24008907
carbohydrates; Chinese; coronary heart disease; glycemic load; refined grains
16.  Fruit and vegetable intake and the risk of colorectal cancer: Results from the Shanghai Men's Health Study 
Cancer causes & control : CCC  2013;24(11):1935-1945.
Purpose
The observed associations of fruit and vegetable consumption with the risk of colorectal cancer have been inconsistent. Therefore, we aimed to evaluate the association of fruit and vegetable consumption with the risk of colorectal cancer within Chinese men.
Methods
61,274 male participants aged 40 to 74 years were included. A validated food frequency questionnaire was administered to collect information on usual dietary intake, including 8 fruits and 38 vegetables commonly consumed by residents of Shanghai. Follow-up for diagnoses of colon or rectal cancer were available through December 31, 2010. Dietary intakes were analyzed both as categorical (quintiles) and continuous variables. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for colorectal, colon, and rectal cancer using Cox proportional hazards models.
Results
After 390,688 person-years of follow-up, 398 cases of colorectal cancer (236 colon and 162 rectal) were observed in the cohort. Fruit consumption was inversely associated with the risk of colorectal cancer (5th vs. 1st quintile HR: 0.67; 95% CI: 0.48, 0.95; P trend = 0.03), whereas vegetable intake was not significantly associated with risk. The associations for sub-groups of fruits and legumes, but not other vegetable categories, were generally inversely associated with the risk of colon and rectal cancer.
Conclusions
Fruit intake was generally inversely associated with the risk of colorectal cancer while vegetable consumption was largely unrelated to risk among middle aged and older Chinese men.
doi:10.1007/s10552-013-0268-z
PMCID: PMC3805771  PMID: 23913012
Colorectal cancer; fruits; vegetables; cohort study; Chinese men
17.  GENOME-WIDE ASSOCIATION STUDY META-ANALYSIS REVEALS TRANS-ETHNIC REPLICATION OF MEAN ARTERIAL AND PULSE PRESSURE LOCI 
Hypertension  2013;62(5):853-859.
We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage-1) followed by replication study of up to 28,783 participants (stage-2). For novel loci, statistical significance was determined by a P<5.0×10−8 in joint analysis of stage-1 and stage-2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of trans-ethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10−3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for trans-ethnic replication including rs17249754 at ATP2B1 (P=7.5×10−15), rs2681492 at ATP2B1 (P=3.4×10−7), rs11191593 at NT5C2 (1.1×10−6), rs3824755 at CYP17A1 (P=1.2×10−6), and rs13149993 at FGF5 (P=2.4×10−4). Two additional variants showed suggestive evidence of trans-ethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10−5) and rs11191593 at NT5C2 (P=1.1×10−3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10−3) and rs2681492 at ATP2B1 (P=9.0×10−3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mmHg for mean arterial pressure and from 0.03 to 0.21 mmHg for pulse pressure. In conclusion, we present the first evidence of trans-ethnic replication of several mean arterial and pulse pressure loci in an East Asian population.
doi:10.1161/HYPERTENSIONAHA.113.01148
PMCID: PMC3972802  PMID: 24001895
genetics; polymorphism; single nucleotide; blood pressure; hypertension; genome-wide association study; meta-analysis
18.  Visceral adiposity and risk of coronary heart disease in relatively lean Chinese adults 
International journal of cardiology  2013;168(3):2141-2145.
Background
The hypertriglyceridemic waist phenotype (defined using both elevated waist circumference and triglycerides) and visceral adiposity index (VAI, defined using waist circumference, body mass index, triglycerides, and high-density lipoprotein cholesterol) have been suggested to be inexpensive yet effective markers of visceral (intra-abdominal) obesity and related dysmetabolic state. These markers may be particularly useful to Asian populations who generally have a low body weight but are prone to visceral adiposity.
Methods
We examined associations of the hypertriglyceridemic waist phenotype and VAI with risk of coronary heart disease (CHD) in a nested case-control study conducted within two prospective cohort studies of Chinese adults. We identified 355 incident cases of CHD and 697controls matched for sex, age, and date and time of baseline sample collection. Anthropometric and lipid measurements were performed and used to define the hypertriglyceridemic waist phenotype and VAI according to published methods. Conditional logistic regression was used to evaluate the associations.
Results
Cases had a higher prevalence of the hypertriglyceridemic waist phenotype and higher VAI score than controls in both sexes. Adjusted odds ratios of CHD associated with hypertriglyceridemic waist were 5.18 (95% CI, 2.46–10.9) and 4.63 (2.03–10.5) for women and men, respectively. Adjusted odds ratios of CHD comparing the highest vs. lowest quartile of VAI were 4.44 (95% CI, 2.24–8.82) and 4.23 (1.99–9.00) for women and men, respectively.
Conclusion
Our study demonstrates, for the first time, that the hypertriglyceridemic waist phenotype and high VAI score are associated with substantially elevated risk of CHD in Chinese men and women.
doi:10.1016/j.ijcard.2013.01.275
PMCID: PMC3701753  PMID: 23453877
visceral adiposity; heart disease; Chinese
19.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
20.  Associations of Tai Chi, Walking, and Jogging With Mortality in Chinese Men 
American Journal of Epidemiology  2013;178(5):791-796.
Moderate-intensity exercise has attracted considerable attention because of its safety and many health benefits. Tai Chi, a form of mind-body exercise that originated in ancient China, has been gaining popularity. Practicing Tai Chi may improve overall health and well-being; however, to our knowledge, no study has evaluated its relationship with mortality. We assessed the associations of regular exercise and specifically participation in Tai Chi, walking, and jogging with total and cause-specific mortality among 61,477 Chinese men in the Shanghai Men's Health Study (2002–2009). Information on exercise habits was obtained at baseline using a validated physical activity questionnaire. Deaths were ascertained through biennial home visits and linkage with a vital statistics registry. During a mean follow-up of 5.48 years, 2,421 deaths were identified. After adjustment for potential confounders, men who exercised regularly had a hazard ratio for total mortality of 0.80 (95% confidence interval: 0.74, 0.87) compared with men who did not exercise. The corresponding hazard ratios were 0.80 (95% confidence interval: 0.72, 0.89) for practicing Tai Chi, 0.77 (95% confidence interval: 0.69, 0.86) for walking, and 0.73 (95% confidence interval: 0.59, 0.90) for jogging. Similar inverse associations were also found for cancer and cardiovascular mortality. The present study provides the first evidence that, like walking and jogging, practicing Tai Chi is associated with reduced mortality.
doi:10.1093/aje/kwt050
PMCID: PMC3755647  PMID: 23813700
Chinese; jogging; mortality; Tai Chi; walking
21.  New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women 
Background
Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations.
Methods
We evaluated nine of those non-replication loci in East Asians in order to identify new risk variants for breast cancer in these regions. First, we analyzed single nucleotide polymorphisms (SNPs) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (Stage 1). In each region we selected a SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (Stage 2). Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants.
Results
Two SNPs were replicated in Stage 2 at P < 0.05: rs1419026 at 6q14 (per allele OR = 1.07, 95% CI: 1.03-1.12, P = 3.0×10−4) and rs941827 at 10q25 (OR = 0.92, 95% CI: 0.89-0.96, P = 5.3×10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR = 0.88, 95% CI: 0.82-0.97, P = 5.3×10−5).
Conclusion
We identified a new breast cancer risk variant at 10q25 in East Asian women.
Impact
Results from this study improve the understanding of the genetic basis for breast cancer.
doi:10.1158/1055-9965.EPI-12-1393
PMCID: PMC3720126  PMID: 23677579
breast cancer; genetic susceptibility; GWAS replication; single nucleotide polymorphism
22.  Fish Intake and Risks of Total and Cause-specific Mortality in 2 Population-based Cohort Studies of 134,296 Men and Women 
American Journal of Epidemiology  2013;178(1):46-57.
Despite a proposed protective effect of fish intake on the risk of cardiovascular disease, epidemiologic evidence on fish intake and mortality is inconsistent. We investigated associations of fish intake, assessed through a validated food frequency questionnaire, with risks of total and cause-specific mortality in 2 prospective cohort studies of 134,296 Chinese men and women (1997–2009). Vital status and date and cause of death were ascertained through annual linkage to the Shanghai Vital Statistics Registry database and biennial home visits. Cox regression was used to calculate hazard ratios and corresponding 95% confidence intervals. After excluding the first year of observation, the analysis included 3,666 deaths among women and 2,170 deaths among men. Fish intake was inversely associated with risks of total, ischemic stroke, and diabetes mortality; the corresponding hazard ratios for the highest quintiles of intake compared with the lowest were 0.84 (95% confidence interval (CI): 0.76, 0.92), 0.63 (95% CI: 0.41, 0.94), and 0.61 (95% CI: 0.39, 0.95), respectively. No associations with cancer or ischemic heart disease mortality were observed. Further analyses suggested that the inverse associations with total, ischemic stroke, and diabetes mortality were primarily related to consumption of saltwater fish and intake of long-chain n-3 fatty acids. Overall, our findings support the postulated health benefits of fish consumption.
doi:10.1093/aje/kws584
PMCID: PMC3816343  PMID: 23788668
China; diet; fish intake; men; mortality; stroke; women
23.  Predictors and Variability of Repeat Measurements of Urinary Phenols and Parabens in a Cohort of Shanghai Women and Men 
Environmental Health Perspectives  2014;122(7):733-740.
Background: Exposure to certain phenols is ubiquitous because of their use in many consumer and personal care products. However, predictors of exposure have not been well characterized in most populations.
Objectives: We sought to identify predictors of exposure and to assess the reproducibility of phenol concentrations across serial spot urine samples among Chinese adults.
Methods: We measured 2,4-dichlorophenol, 2,5-dichlorophenol, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, bisphenol A, and triclosan in urine collected during 1997–2006 from 50 participants of the Shanghai Women’s Health Study cohort and during 2002–2006 from 50 participants of the Shanghai Men’s Health Study cohort. We investigated predictors of concentrations using the Satterthwaite t-test, and assessed reproducibility among serial samples using intraclass correlation coefficients (ICCs) and Spearman correlation coefficients (SCCs).
Results: Creatinine-corrected phenol concentrations were generally higher among women than men. Participants who had taken medicine within the previous 24 hr had higher concentrations of propyl paraben. Cigarette smoking was associated with lower concentrations of propyl and methyl parabens among men. Bottled water consumption was associated with higher bisphenol A, 2,4-dichlorophenol, and 2,5-dichlorophenol concentrations among women. Among men, reproducibility across serial samples was moderate for 2,4-dichlorophenol and 2,5-dichlorophenol (ICC = 0.54–0.60, SCC = 0.43–0.56), but lower for other analytes (ICC = 0.20–0.29). Reproducibility among women was low (ICC = 0.13–0.39), but increased when restricted to morning-only urine samples.
Conclusions: Among these 100 Shanghai residents, urinary phenol concentrations varied by sex, smoking, and consumption of bottled water. Our results suggest that a single urine sample may be adequate for ranking exposure to the precursors of 2,4-dichlorophenol and 2,5-dichlorophenol among men and, under certain circumstances, among women.
Citation: Engel LS, Buckley JP, Yang G, Liao LM, Satagopan J, Calafat AM, Matthews CE, Cai Q, Ji BT, Cai H, Engel SM, Wolff MS, Rothman N, Zheng W, Xiang YB, Shu XO, Gao YT, Chow WH. 2014. Predictors and variability of repeat measurements of urinary phenols and parabens in a cohort of Shanghai women and men. Environ Health Perspect 122:733–740; http://dx.doi.org/10.1289/ehp.1306830
doi:10.1289/ehp.1306830
PMCID: PMC4080538  PMID: 24659570
24.  Elevated 4-Aminobiphenyl and 2, 6-Dimethylaniline Hemoglobin Adducts and Increased Risk of Bladder Cancer among Lifelong Nonsmokers - The Shanghai Bladder Cancer Study 
Background
4-Aminobiphenyl (ABP) is an established human bladder carcinogen, with tobacco smoke being a major source of human exposure. Other arylamine compounds, including 2,6-dimethylaniline (2,6-DMA), have been implicated as possible human bladder carcinogens. Hemoglobin adducts of 4-ABP and 2,6-DMA are validated biomarkers of exposure to those compounds in humans.
Methods
The Shanghai Bladder Cancer Study enrolled 581 incident bladder cancer cases and 604 population controls. Each participant was solicited for his/her history of tobacco use and other lifestyle factors, and donation of blood and urine specimens. Red blood cell lysates were used to quantify both hemoglobin adducts of 4-ABP and 2,6-DMA. Urine samples were used to quantify total cotinine. Odds ratios (ORs) and 95% confidence intervals (CIs) for bladder cancer were estimated using unconditional logistic regression methods.
Results
Among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for low (below median of positive values) and high versus undetectable levels of 2,6-DMA hemoglobin adducts were 3.87 (1.39-10.75) and 6.90 (3.17-15.02), respectively (Ptrend<0.001). Similarly, among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for 3rd and 4th versus 1st/2nd quartiles of 4-ABP hemoglobin adducts was 1.30 (0.76-2.22) and 2.29 (1.23-4.24), respectively (Ptrend=0.00). The two associations were independent of each other.
Conclusion
Hemoglobin adducts of 4-ABP and 2,6-DMA were significantly and independently associated with increased bladder cancer risk among lifelong nonsmokers in Shanghai, China.
Impact
The findings of the present study in China with previous data in Los Angeles, California strongly implicate arylamines as potential causal agents of human bladder cancer.
doi:10.1158/1055-9965.EPI-12-1447
PMCID: PMC4065796  PMID: 23539508
25.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825

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