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1.  Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population 
Chinese journal of cancer  2013;33(2):68-73.
Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02–1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17–2.14; OR = 1.51, 95% CI: 1.09–2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interactions with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12–1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.
PMCID: PMC3884064  PMID: 23816557
Pancreatic ductal adenocarcinoma; ABO gene; genome-wide association study; genetic variation; haplotype
2.  Variants in CCK and CCKAR genes to susceptibility to biliary tract cancers and stones: a population-based study in Shanghai, China 
Journal of gastroenterology and hepatology  2013;28(9):10.1111/jgh.12278.
Background and Aim
Altered motility of the gallbladder is associated with an increased risk of gallstones and can result in biliary tract cancers. Cholecystokinin (CCK) is an important modulator of gallbladder motility which functions by activating CCK type-A receptor (CCKAR). The aim of this study was to determine whether genetic variants in CCK and CCKAR are associated with the risk of biliary tract cancers and stones.
We investigated the associations between 9 single nucleotide polymorphisms (SNPs) in CCK and CCKAR in a population-based case-control study, including 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in Shanghai, China.
We found that women with the CCKAR rs1800855 AA genotype had an increased risk of gallbladder cancer (odd ratio (OR) =2.37, 95% confidence interval (CI): 1.36–4.14) compared to subjects with the TT genotype, and remained significant after Bonferroni correction (P=0.0056). Additionally, female carriers of the CCKAR haplotype C-T-C-T (rs2071011-rs915889-rs3822222-rs1800855) had a reduced risk of gallbladder cancer (OR=0.61, 95%CI: 0.43–0.86) compared to those with the G-C-C-A haplotype, the association also remained significant after Bonferroni correction.
These findings suggest that variants in the CCKAR gene may influence the risk of gallbladder cancer in women. Additional studies are needed to confirm our findings.
PMCID: PMC3820582  PMID: 23701593
biliary tract cancer; gallstone; CCK and CCKAR; variant; haplotype; susceptibility
3.  Great success, further progress 
PMCID: PMC4202459  PMID: 25333043
4.  Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women 
Journal of Clinical Oncology  2013;31(12):1548-1553.
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.
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.
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.
PMCID: PMC3625711  PMID: 23530109
5.  Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population 
Chinese Journal of Cancer  2014;33(2):68-73.
Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.
PMCID: PMC3884064  PMID: 23816557
Pancreatic ductal adenocarcinoma; ABO gene; genome-wide association study; genetic variation; haplotype
6.  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.
PMCID: PMC4232456  PMID: 24916784
diet; dietary supplements; lung neoplasm; prospective study; tocopherols; women
7.  Urinary Levels of N-Nitroso Compounds in Relation to Risk of Gastric Cancer: Findings from the Shanghai Cohort Study 
PLoS ONE  2015;10(2):e0117326.
N-Nitroso compounds are thought to play a significant role in the development of gastric cancer. Epidemiological data, however, are sparse in examining the associations between biomarkers of exposure to N-nitroso compounds and the risk of gastric cancer.
A nested case-control study within a prospective cohort of 18,244 middle-aged and older men in Shanghai, China, was conducted to examine the association between urinary level of N-nitroso compounds and risk of gastric cancer. Information on demographics, usual dietary intake, and use of alcohol and tobacco was collected through in-person interviews at enrollment. Urinary levels of nitrate, nitrite, N-nitroso-2-methylthiazolidine-4-carboxylic acid (NMTCA), N-nitrosoproline (NPRO), N-nitrososarcosine (NSAR), N-nitrosothiazolidine-4-carboxylic acid (NTCA), as well as serum H. pylori antibodies were quantified in 191 gastric cancer cases and 569 individually matched controls. Logistic regression method was used to assess the association between urinary levels of N-nitroso compounds and risk of gastric cancer.
Compared with controls, gastric cancer patients had overall comparable levels of urinary nitrate, nitrite, and N-nitroso compounds. Among individuals seronegative for antibodies to H. pylori, elevated levels of urinary nitrate were associated with increased risk of gastric cancer. The multivariate-adjusted odds ratios for the second and third tertiles of nitrate were 3.27 (95% confidence interval = 0.76–14.04) and 4.82 (95% confidence interval = 1.05–22.17), respectively, compared with the lowest tertile (P for trend = 0.042). There was no statistically significant association between urinary levels of nitrite or N-nitroso compounds and risk of gastric cancer. Urinary NMTCA level was significantly associated with consumption of alcohol and preserved meat and fish food items.
The present study demonstrates that exposure to nitrate, a precursor of N-nitroso compounds, may increase the risk of gastric cancer among individuals without a history of H. pylori infection.
PMCID: PMC4319940  PMID: 25658333
8.  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.
PMCID: PMC4127632  PMID: 25038754
9.  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.
PMCID: PMC4310680  PMID: 20043258
10.  Calibrating a population-based job-exposure matrix using inspection measurements to estimate historical occupational exposure to lead for a population-based cohort in Shanghai, China 
The epidemiologic evidence for the carcinogenicity of lead is inconsistent and requires improved exposure assessment to estimate risk. We evaluated historical occupational lead exposure for a population-based cohort of women (n=74,942) by calibrating a job-exposure matrix (JEM) with lead fume (n=20,084) and lead dust (n=5,383) measurements collected over four decades in Shanghai, China. Using mixed-effect models, we calibrated intensity JEM ratings to the measurements using fixed-effects terms for year and JEM rating. We developed job/industry-specific estimates from the random-effects terms for job and industry. The model estimates were applied to subjects’ jobs when the JEM probability rating was high for either job or industry; remaining jobs were considered unexposed. The models predicted that exposure increased monotonically with JEM intensity rating and decreased 20–50-fold over time. The cumulative calibrated JEM estimates and job/industry-specific estimates were highly correlated (Pearson correlation=0.79–0.84). Overall, 5% of the person-years and 8% of the women were exposed to lead fume; 2% of the person-years and 4% of the women were exposed to lead dust. The most common lead-exposed jobs were manufacturing electronic equipment. These historical lead estimates should enhance our ability to detect associations between lead exposure and cancer risk in future epidemiologic analyses.
PMCID: PMC3508334  PMID: 22910004
lead; cancer; exposure assessment; occupational exposure; job exposure matrix; mixed-effects model
11.  Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes 
Annals of human genetics  2014;78(1):23-32.
We used a two-stage study design to evaluate whether variations in the peroxisome proliferator-activated receptors (PPAR) and the peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with T2D risk. Stage I used data from a genome-wide association study (GWAS) from Shanghai, China (1,019 T2D cases and 1,709 controls) and from a meta-analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN-T2D). Criteria for selection of SNPs for stage II were: 1) P<0.05 in single marker analysis in Shanghai GWAS and P<0.05 in the meta-analysis or 2) P<10−3 in the meta-analysis alone and 3) minor allele frequency ≥0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle-aged men and women from Shanghai with 1,700 T2D cases and 1,647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR=0.87; 95% CI: 0.77–0.99). Gene-body mass index (BMI) and gene-exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2,719 cases and 3,356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed.
PMCID: PMC3936468  PMID: 24359475
type 2 diabetes; PPAR; PGC1
12.  Helicobacter pylori Seropositivities and Risk of Pancreatic Carcinoma 
Pathophysiologic actions of Helicobacter pylori colonization on gastric acidity have been hypothesized to modulate the effect of pancreatic carcinogens, through CagA-negative organism strain type, hyperchlorhydria and increased risk of pancreatic cancer, or CagA-positive strain, hypochlorhydria and decreased risk of pancreatic cancer. We aimed to determine H. pylori strain-specific associations with pancreatic cancer in a population where colonization by CagA-positive strains is common.
We carried out a large population-based case-control study of pancreatic carcinoma in Shanghai, China. Venipuncture specimens were obtained from a representative sample of 761 case patients and 794 randomly selected control subjects matched by category of age and gender. Antibody seropositivity for H. pylori and its virulence protein CagA were determined by commercial enzyme-linked immunosorbent IgG assays.
Compared to individuals seronegative for both H. pylori and CagA, decreased pancreas-cancer risk was seen for CagA seropositivity (adjusted odds ratio [OR], 0.68; 95% confidence interval (CI), 0.54–0.84), while some increased risk was suggested for CagA-negative H. pylori seropositivity (OR, 1.28; 95% CI, 0.76–2.13). No risk interactions were observed between CagA seropositivity and gender, cigarette smoking, or age-21 body mass index.
Similar to what has been seen in animal models, our results provide suggestive evidence in humans for the involvement of gastric acidity, through its bidirectional modification according to colonization by Helicobacter pylori CagA strain type, in the risk of pancreatic carcinoma.
Helicobacter pylori colonization may have diverse effects on cancer risk, depending on the organism strain type as well as on the particular cancer site.
PMCID: PMC3947155  PMID: 24234587
Cytotoxin-associated gene A; Case-control Studies; H. pylori; Pancreatic Cancer
13.  Menstrual and reproductive factors and gastric cancer risk in a large prospective study of women 
Gut  2007;56(12):1671-1677.
Gastric cancer incidence rates are consistently lower in women than men in both high and low‐risk regions worldwide. Sex hormones, such as progesterone and estrogen, may protect women against gastric cancer.
To investigate the association of menstrual and reproductive factors and gastric cancer risk.
These associations were prospectively investigated in 73 442 Shanghai women. After 419 260 person‐years of follow‐up, 154 women were diagnosed with gastric cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models adjusted for age, body mass index, education, income, and cigarette use.
No associations were observed between gastric cancer risk and age of menarche, number of children, breast feeding, or oral contraceptive use. In contrast, associations were observed with age of menopause (HR 0.80 per five‐year increase in menopausal age, 95% CI 0.66–0.97), years of fertility (participants with less than 30 years of fertility were at increased risk compared with those with 30–36 years of fertility, HR 1.90, 95% CI 1.25–2.90), years since menopause (HR 1.26 per five years, 95% CI 1.03–1.53), and intrauterine device use (HR for users 1.61, 95% CI 1.08–2.39).
These results support the hypothesis that female hormones play a protective role in gastric cancer risk.
PMCID: PMC2095686  PMID: 17627962
stomach neoplasms; cohort studies; prospective studies; hormones
14.  Impact of Post-Diagnosis Smoking on Long-Term Survival of Cancer Patients: The Shanghai Cohort Study 
Cancer is the number one cause of death among men in China. Cigarette smoking is the most preventable cause of cancer. Data on the impact of continued smoking after cancer diagnosis on survival of cancer patients are sparse.
We studied the association between post-diagnosis smoking and risk of all-cause death among 1,632 incident cancer patients in the Shanghai Cohort Study, a population-based prospective cohort of 18,244 men in Shanghai. The change of smoking status after baseline interview was ascertained through annual in-person interviews. Cox proportional hazards regression models were used to estimate hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality associated with change in smoking status.
Patients who continued smoking after cancer diagnosis experienced a statistically significant 59% (95% CI = 36–86%) increase in risk of death compared with cancer patients who did not smoke after cancer diagnosis. Among current smokers at cancer diagnosis, HRs (95% CIs) were 1.79 (1.49–2.16) in all cancer patients, 2.36 (1.63–3.42) in lung cancer patients, 1.63 (0.98–2.73) in stomach cancer patients, 2.31 (1.40–3.81) in colorectal cancer patients, and 2.95 (1.09–7.95) in bladder cancer patients who continued smoking compared with their counterparts who stopped smoking after cancer diagnosis.
Post-diagnosis cigarettes smoking significantly increased the risk of death for male cancer patients.
These data provide new information regarding smoking and cancer survival, which should inform future research into the contextual and individual-level barriers that may result in inadequate attention of smoking among cancer patients in the post-diagnosis setting.
PMCID: PMC3919701  PMID: 24319070
15.  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.
PMCID: PMC4068797  PMID: 24836286
16.  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.
PMCID: PMC3888273  PMID: 24008907
carbohydrates; Chinese; coronary heart disease; glycemic load; refined grains
17.  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.
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.
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.
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.
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.
PMCID: PMC3805771  PMID: 23913012
Colorectal cancer; fruits; vegetables; cohort study; Chinese men
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.
PMCID: PMC3972802  PMID: 24001895
genetics; polymorphism; single nucleotide; blood pressure; hypertension; genome-wide association study; meta-analysis
19.  Polycyclic aromatic hydrocarbons and risk of gastric cancer in the Shanghai Women’s Health Study 
Purpose: Polycyclic aromatic hydrocarbons (PAHs) are byproducts of incomplete combustion of organic materials. Sources include tobacco smoke, charbroiled meat, and air pollution. Indirect evidence suggests that PAHs may be associated with carcinogenesis, but the association with gastric cancer is unclear. Methods: Using a nested case-control study design, we examined prediagnostic urinary concentrations of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite, in 153 gastric cancer cases and 306 matched controls within the Shanghai Women’s Health Study. Conditional logistic regression adjusted for potential risk factors was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: Urinary 1-OHPG concentrations were slightly higher among cases than controls, with medians of 0.29 μmol/mol Cr (interquartile range, 0.16-0.48) and 0.24 μmol/mol Cr (interquartile range, 0.12-0.45), respectively. Increasing concentrations of 1-OHPG appeared to be associated with elevated risk of gastric cancer, but not within the highest category of 1-OHPG (Q4 vs Q1: OR = 1.4; 95% CI = 0.8-2.5). Conclusions: Our findings suggest that higher concentrations of 1-OHPG are related to gastric cancer risk, but no clear dose-response relationship was observed.
PMCID: PMC4214261  PMID: 25379133
1-hydroxypyrene glucuronide; polycyclic aromatic hydrocarbons; gastric cancer; China
20.  Visceral adiposity and risk of coronary heart disease in relatively lean Chinese adults 
International journal of cardiology  2013;168(3):2141-2145.
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.
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.
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.
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.
PMCID: PMC3701753  PMID: 23453877
visceral adiposity; heart disease; Chinese
21.  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.
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.
PMCID: PMC3879410  PMID: 23841909
Liver cancer; dietary patterns; food groups; vegetables; prospective study
22.  No Association between Genetic Variants in Angiogenesis and Inflammation Pathway Genes and Breast Cancer Survival among Chinese Women 
Cancer epidemiology  2013;37(5):619-624.
Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown.
A two-stage candidate pathway association study was conducted among 6,983 Chinese women. Stage 1 included 2,884 women followed for a median of 5.7 years; Stage 2 included 4,099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS).
Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study.
No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer.
Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.
PMCID: PMC4064366  PMID: 23850146
breast cancer survival; genetic variants; angiogenesis genes; inflammation pathway genes; Chinese women
23.  Prediagnostic levels of serum one-carbon metabolites and risk of hepatocellular carcinoma 
Rats fed diets deficient in choline develop hepatocellular carcinoma (HCC). Tumor DNA from these animals is characteristically hypomethylated, suggesting that disruption of the one-carbon metabolism pathway is an underlying mechanism for hepatocarcinogenesis. Prospective studies in humans on circulating choline and other one-carbon metabolites and HCC risk have been lacking.
We prospectively examined the association between prediagnostic serum concentrations of one-carbon metabolites including betaine, choline, cystathionine, homocysteine, methionine, 5-methyltetrahydrofolate (5-MTHF), pyridoxal-5-phosphate (PLP, the bioactive form of vitamin B6) and S-adenosylmethionine (SAM), and risk of developing HCC based on a nested case-control study of 297 incident cases and 631 matched controls from a cohort of 18,244 men in Shanghai, China. Logistic regression methods were used to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for established risk factors for HCC.
Serum choline and PLP were associated with statistically significant reduced risk of HCC, while serum cystathionine, methionine and SAM were associated with increased HCC risk (all Ptrend<0.05). The inverse associations for HCC risk with choline and PLP remained statistically significant after adjusting for all potential confounders. The multivariate-adjusted ORs (95% CIs) for the highest versus lowest quintiles of serum choline and PLP were 0.35 (0.16, 0.78) (P=0.010) and 0.44 (0.25, 0.78) (P=0.005), respectively. There were no associations for HCC risk with 5-MTHF, betaine, or homocysteine.
The inverse associations between choline and vitamin B6 and the risk of HCC development are novel and warrant further investigation.
Identifying new modifiable factors for HCC prevention are warranted.
PMCID: PMC3928816  PMID: 23897582
choline; hepatocellular carcinoma; one-carbon metabolism; vitamin B6
24.  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.
PMCID: PMC4169232  PMID: 23143601
25.  Age at Menarche and Natural Menopause and Number of Reproductive Years in Association with Mortality: Results from a Median Follow-Up of 11.2 Years among 31,955 Naturally Menopausal Chinese Women 
PLoS ONE  2014;9(8):e103673.
Studies conducted in Western countries suggest that early age at menarche and early age at menopause are both associated with increased total mortality, but limited data are available for Asian populations. We examined associations of age at menarche and natural menopause and duration of the reproductive span with mortality in a population-based cohort study of Chinese women.
We evaluated the effects of age at menarche, age at natural menopause, and number of reproductive years on total and cause-specific mortality among 31,955 naturally menopausal Chinese women who participated in the Shanghai Women's Health Study, a population-based, prospective cohort study.
A total of 3,158 deaths occurred during a median follow-up of 11.2 years. Results from Cox proportional hazards models showed that younger age at menopause (<46.64 years) was associated with higher risk of total mortality (Ptrend  = 0.02). Younger age at menarche (<14 years) was associated with higher risk of mortality from stroke (Ptrend  = 0.03) and diabetes (Ptrend = 0.02) but lower risk of mortality from respiratory system cancer (Ptrend  = 0.01). Women with a shorter reproductive span had lower risk of mortality from gynecological cancers (Ptrend = 0.03).
Our study found that menstrual characteristics are important predictors of mortality, suggesting an important role of sex hormones in biological aging.
PMCID: PMC4121137  PMID: 25090234

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