[Show abstract][Hide abstract] ABSTRACT: Choline deficiency has been shown to induce liver fat accumulation in both rodent and human studies. However, it is unclear whether dietary choline intake is related to fatty liver in the general population.
[Show abstract][Hide abstract] ABSTRACT: Background: We previously reported that higher levels of mitochondrial DNA copy number (mtDNA CN) were associated with lung cancer risk among male heavy smokers (i.e., ≥20 cigarettes per day) in the Alpha-Tocopherol Beta-Carotene (ATBC) study. Here, we present two additional prospective investigations nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and the Shanghai Women's Health Study (SWHS), and pooled with previously published data from ATBC. Materials and Methods: All DNA was extracted from peripheral whole blood samples using the phenol-chloroform method, and mtDNA CN was assayed by fluorescence-based quantitative polymerase chain reaction. Multivariate unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association of mtDNA CN and lung cancer risk. Results: Overall, mtDNA CN was not associated with lung cancer risk in the PLCO, SWHS, or pooled populations (all P-trends > 0.42, P-heterogeneity = 0.0001), and mtDNA CN was inversely associated with lung cancer risk among male smokers in PLCO, the opposite direction observed in ATBC. Additionally, the mtDNA CN association observed among male heavy smokers in ATBC was the opposite direction in PLCO. Conclusion: mtDNA CN was not consistently associated with lung cancer risk across three prospective study populations from Europe, Asia, and the US. Impact: This pooled study suggests no consistent association between pre-diagnostic mtDNA CN levels and lung cancer risk across several populations.
[Show abstract][Hide abstract] ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. Dual specificity phosphatase 4 (DUSP4) has recently been suggested as a potential marker of chemotherapy resistance for TNBC. DUSP4 gene expression levels were measured in breast cancer tissue from 469 TNBC patients aged 20-75 years who participated in the Shanghai Breast Cancer Survival Study, and their association with recurrence/breast cancer mortality and total mortality was evaluated. Information on breast cancer diagnosis, treatment, and disease progression was collected via medical chart review and multiple in-person follow-up surveys. A Cox regression model was applied in the data analyses. Over a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of transcript variant 1 (NM_001394) and transcript variant 2 (NM_057158) of the DUSP4 gene were studied and were highly correlated (r = 0.76). Low DUSP4 expression levels, particularly of variant 1, were associated with both increased recurrence/breast cancer mortality and increased overall mortality. Hazard ratios with adjustment for age at diagnosis and TNM stage associated with below versus above the median expression level were 1.97 (95 % confidence interval (CI): 1.27-3.05) for recurrence/breast cancer mortality and 2.09 (95 % CI: 1.38-3.17) for overall mortality. Additional adjustment for expression levels of MKI67 and TP53, common treatment types, breast cancer subtype, and grade did not materially alter the observed associations. Low DUSP4 expression levels predict recurrence and mortality in TNBC patients independently from known clinical and molecular predictors.
Breast Cancer Research and Treatment 10/2014; · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Levels of the cyclooxygenase 2 (COX-2) enzyme are elevated in breast cancer tissue, and most COX-2 effects are believed to be mediated through overproduction of prostaglandin-E2 (PGE2). We evaluated associations between the primary urinary metabolite of PGE2 (PGE-M) and breast cancer risk. Methods. A nested case-control study of 504 cases and 1,082 controls was conducted using data from the Shanghai Women's Health Study, a large population-based prospective cohort study of 74,941 Chinese women. Urinary PGE-M was measured using a liquid chromatography/tandem mass spectrometric method. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (95%CI), with adjustment for potential confounders. Results. Overall, no association between urinary PGE-M and breast cancer was detected. However, a suggestive positive association was found among postmenopausal women. In particular, a clear dose-response relationship between urinary PGE-M and breast cancer was observed among postmenopausal women with a BMI<25 kg/m2 (P for linear trend = 0.005). Among these women, risk of breast cancer increased from 1.00 (reference) to 1.06 (95% CI: 0.56-1.99), 1.50 (95% CI: 0.79-2.83), and 2.32 (95% CI: 1.24-4.41) for the lowest to highest quartiles of PGE-M, and such associations were stronger among those who were diagnosed with cancer within the first 4 years of sample collection. No apparent association was observed among overweight postmenopausal women (BMI≥25 kg/m2). Conclusion. High urinary PGE-M level was associated with elevated risk of breast cancer among normal weight, postmenopausal women. Impact. Urinary PGE-M level may be useful for breast cancer risk assessment among normal weight, postmenopausal women.
[Show abstract][Hide abstract] ABSTRACT: The kidney-specific sodium-potassium-chloride cotransporter (NKCC2) protein encoded by solute carrier family 12 member 1 (SLC12A1) is the direct downstream effector of the inward-rectifier potassium channel (ROMK) encoded by potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), both of which are critical for calcium reabsorption in the kidney.
[Show abstract][Hide abstract] ABSTRACT: Background: Mitochondria play an important role in cellular energy metabolism, free radical production, and apoptosis and thus may be involved in cancer development. Methods: We evaluated mtDNA copy number in peripheral leukocytes in relation to CRC risk in a case-control study of 444 CRC cases and 1,423 controls nested in the Shanghai Women's Health Study, a population-based, prospective cohort study. Relative mtDNA copy number was determined by a quantitative real-time PCR assay using peripheral leukocyte DNA samples collected at the time of study enrollment, prior to cancer diagnosis. Results: We found that baseline mtDNA copy number was lower among women who subsequently developed CRC (geometric mean = 0.277, 95% CI: 0.269-0.285) than among women who remained cancer-free (geometric mean = 0.288, 95% CI: 0.284-0.293; P=0.0153). Multivariate adjusted odds ratios (ORs) were 1.26 (95% CI: 0.93-1.70) and 1.44 (95% CI: 1.06-1.94) for the middle and lower tertiles of mtDNA copy number, respectively, compared with the upper tertile (highest mtDNA copy number; P for trend=0.0204). The association varied little by the interval between blood collection and cancer diagnosis. Conclusions: Our data suggest that mtDNA copy number measured in peripheral leukocytes may be a potential biomarker useful for CRC risk assessment. Impact: If confirmed, mtDNA copy number measured in peripheral leukocytes may be a biomarker useful for colorectal cancer risk assessment.
[Show abstract][Hide abstract] ABSTRACT: To assess correlations between cruciferous vegetable intake and urinary isothiocyanate (ITC) level, in addition to glutathione S-transferase (GST) genotypes and other individual factors.
[Show abstract][Hide abstract] ABSTRACT: In large scale population-based whole-exome sequencing (WES) studies, there are some samples occasionally sequenced two or more times due to a variety of reasons. To investigate how to efficiently utilize these duplicated sequencing data, we conducted comprehensive evaluation of variant calling strategies. 92 samples subjected to WES twice were selected from a large population study. These 92 duplicated samples were divided into two groups: group H consisting of the higher sequencing depth for each subject and group L consisting of the lower depth for each subject. The merged samples for each subject were put in a third group M. Using the GATK multisample toolkit, we compared variant calling accuracy among three strategies. Hierarchical clustering analysis indicated that the two replicates for each subject showed high homogeneity. The comparative analyses on the basis of heterozygous-homozygous ratio (Hete/Homo), transition-transversion ratio (Ti/Tv), and overlapping rate with the 1000 Genomes Project consistently showed that the data quality of the SNPs detected from the M group was more accurate than that of SNPs detected from the H and L groups. These results suggested that merging homogeneous duplicated exomes instead of using one of them could improve variant calling accuracy.
BioMed Research International 08/2014; 2014(2014):7. · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10-94<P<5×10-8, odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2×10-23 < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.
[Show abstract][Hide abstract] ABSTRACT: Experimental studies have provided evidence that isothiocyanates (ITCs) from cruciferous vegetables may modulate carcinogen metabolism and facilitate carcinogen detoxification and reduce cancer risk. However, no epidemiological studies on liver cancer were reported. This study investigates the association between urinary ITCs levels and liver cancer risk among men and women in Shanghai, China. A nested case-control study of 217 incident cases of liver cancer and 427 matched controls identified from the Shanghai Women's Health Study and Shanghai Men's Health Study was conducted. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) summarizing the association between urinary ITCs levels and liver cancer risk. Compared to those with undetectable ITCs, nonsignificantly inverse association was observed among detectable (OR = 0.80; 95% CI = 0.51-1.26), below-median (OR = 0.76; 95% CI = 0.47-1.24), and above-median concentration (OR = 0.86; 95% CI = 0.52-1.41) with liver cancer risk. Similar patterns were observed when urinary ITCs levels were categorized into tertiles or quartiles. Although our study firstly focused on the association between urinary ITCs exposure and liver cancer risk, we did not find significant results. Future multicenter prospective, different population studies are warranted to validate our findings.
Nutrition and Cancer 07/2014; · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,8 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4950 at q32. (in intron 2 of the ZC3H11A gene; P = 8.82 × 0 −9), rs0474352 at 5q4.3 (near the ARRDC3 gene; P = .67 × 0 −9) and rs2290203 at 5q26. (in intron 4 of the PRC1 gene; P = 4.25 × 0 −8). We replicated these associations in 6,003 cases and 4,335 controls of European ancestry (P = 0.030, 0.004 and 0.00, respectively). Data from the ENCODE Project suggest that variants rs4950 and rs0474352 might 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. Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have a substantial role in breast cancer etiology 1,2 . Thus far, genome-wide association studies (GWAS) have identified approximately 75 genetic loci associated with breast cancer risk 2–5 . With the exception of the studies we have conducted among East Asian women 6–9 and one study conducted among women of African ancestry 10 , all other published GWAS have been conducted among women of European ancestry. Genetic risk variants identified thus far from GWAS explain only about 10% of familial risk for breast cancer in East Asian women 3 . Given the dif-ferences in genetic architecture and environmental exposures for women of European and East Asian ancestry, additional GWAS need to be conducted among East Asian women to study the genetic basis of breast cancer risk. The current study was conducted as part of the Asia Breast Cancer Consortium (ABCC) to search for additional susceptibility loci for breast cancer. Included in this study are data obtained from 22,780 breast cancer cases and 24,181 controls who were recruited in 14 studies conducted in multiple Asian countries (Supplementary Table 1). The discovery stage (stage 1) included 2 GWAS in which 5,285 Chinese women (SBCGS-1) and 4,777 Korean women (SeBCS1) were scanned primarily using Affymetrix Genome-Wide Human SNP Array 6.0, which consists of 906,602 SNPs. After applying quality control filters described previously 6,9,11 , 5,152 Chinese women (2,867 cases and 2,285 controls; 677,157 SNPs) and 4,298 Korean women (2,246 cases and 2,052 controls; 555,117 SNPs) remained in the cur-rent analysis. Imputation was conducted for each study following the MACH algorithm 12 using HapMap 2 release 22 CHB (Han Chinese in Beijing, China) and JPT (Japanese in Tokyo, Japan) data (2,416,663 SNPs) as the reference. Only SNPs with a high imputation quality score (RSQR ≥ 0.50) were analyzed for associations with breast can-cer risk. In the analyses of data from Chinese and Korean women, a total of 1,930,412 and 1,907,146 SNPs, respectively, were included. A meta-analysis of these GWAS data was conducted using a fixed-effects, inverse variance meta-analysis with the METAL program 13 . There was little evidence of inflation in the association test statis-tics for the studies included in stage 1 (genomic inflation factors (λ): λ = 1.0426 for SBCGS-1, λ = 1.0431 for SeBCS1 and λ = 1.0499 for both studies combined; Supplementary Fig. 1). When scaled to a study of 1,000 cases and 1,000 controls, λ 1,000 values were 1.02, 1.02 and 1.01, respectively. To select SNPs for stage 2 replication, we used the following criteria: (i) association P < 0.05 in the stage 1 meta-analysis results; (ii) the
[Show abstract][Hide abstract] ABSTRACT: Chronic inflammation is associated with increased risk of multiple cancers, including breast cancer. Adipose tissues produce proinflammatory cytokines, and obesity is a risk factor for postmenopausal breast cancer. We evaluated the association of regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk, overall and by body mass index (BMI) and tumor subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. We conducted a population-based, case-control study involving 5,078 women aged 25-75 years who were recruited primarily from the Nashville metropolitan area of Tennessee. Multivariate unconditional logistic regression models were used to estimate odds ratios and 95 % confidence intervals for breast cancer risk after adjusting for multiple potential confounding factors. Regular use of any NSAID was associated with significantly reduced breast cancer risk (OR 0.78; 95 % CI 0.69-0.89). This association was observed for regular use of baby aspirin only (OR 0.82, 95 % CI 0.69-0.99), other NSAIDs only (OR 0.81, 95 % CI 0.69-0.95), and both baby aspirin and other NSAIDs (OR 0.52, 95 % CI 0.40-0.69). These significant inverse associations were found among overweight women (BMI ≥25 kg/m(2)) overall and by subtypes of breast cancer, but not among women with BMI <25 kg/m(2) (P for interaction = 0.023). Regular use of NSAIDs was inversely associated with breast cancer risk, particularly among overweight women. Overweight women may benefit more from the protective effects of NSAID use than normal-weight women.
Breast Cancer Research and Treatment 07/2014; · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A higher adherence to dietary recommendations, such as the Dietary Approaches to Stop Hypertension (DASH) and the Alternative Healthy Eating Index (AHEI), has been associated with lower morbidity and mortality from chronic diseases in Western populations. However, the health benefits of following the Dietary Guidelines for Chinese remain unknown.OBJECTIVE: We examined adherence to the Chinese Food Pagoda (CHFP) in association with total and cause-specific mortality and compared associations with those of the DASH and AHEI.DESIGN: Participants included 61,239 men and 73,216 women (aged 40-74 y) from 2 population-based prospective studies in Shanghai, China. Habitual dietary intakes were assessed at baseline in-person interviews by using validated food-frequency questionnaires. Deaths and underlying causes were identified through the Shanghai Vital Statistics Registry and follow-up home visits.RESULTS: We documented 2954 deaths in men and 4348 deaths in women during mean follow-ups of 6.5 and 12.0 y, respectively. A higher CHFP score was associated with lower total mortality with multivariable-adjusted HRs of 0.67 (95% CI: 0.60, 0.75) in men and 0.87 (95% CI: 0.80, 0.95) in women when extreme quartiles were compared (both P-trend < 0.005). Decreased risks associated with a higher CHFP score were observed for cardiovascular disease, cancer, and diabetes mortality, particularly in men. A significantly lower total mortality was shown for adherence to specific recommendations on vegetables, fruit, legumes, fish, and eggs but not grains, dairy, meat, fat, and salt. A higher DASH score and AHEI also predicted lower mortality from all causes, cardiovascular disease, and diabetes but not cancer.CONCLUSIONS: A greater compliance with Chinese or US dietary guidelines is associated with lower total mortality in Chinese adults. Favorable associations are more evident in men than women and more consistent for cardiometabolic mortality than cancer mortality.
American Journal of Clinical Nutrition 06/2014; · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46,450 cases and 42,600 controls) and analysed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 (rs1053338, per-allele OR=1.07, 95%CI=1.04-1.10, P=2.9x10(-6)), AKAP9-M463I at 7q21 (rs6964587, OR=1.05, 95%CI=1.03-1.07, P=1.7x10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR=1.10, 95%CI=1.07-1.12, P=5.1x10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine GWAS: for ATXN7-K264R, OR=1.07 (95%CI=1.05-1.10, P=1.0x10(-8)); for AKAP9-M463I, OR=1.05 (95%CI=1.04-1.07, P=2.0x10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known genome-wide association study (GWAS) hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Human Molecular Genetics 06/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2,156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n=39,067 cases; n=42,106 controls). SNPs in TACC2 (rs17550038: odds ratio (OR)=1.24, 95% CI 1.16-1.33, p=4.2x10(-10)) and EIF3H (rs799890: OR=1.07, 95% confidence interval (CI) 1.04-1.11, p=8.7x10(-6)) were significantly associated with risk of low grade breast cancer. The TACC2 signal was retained (rs17550038: OR=1.15, 95% CI 1.07-1.23, p=7.9x10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high grade breast cancer risk (p=2.1x10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
Human Molecular Genetics 06/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 [times] 10-8 to 9.22 [times] 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 transcriptional 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-associated loci. Our study provides insights into the genetic basis of CRC and suggests the in
[Show abstract][Hide abstract] ABSTRACT: Epidemiologic studies of occupational lead exposure have suggested increased risks of cancers of the brain, kidney, lung, meninges, and stomach; however, the totality of the evidence is inconsistent. To clarify whether lead is a carcinogen, we investigated the relationship between occupational lead exposure and risks of these five cancer sites in two prospective cohort studies in Shanghai, China.
Occupational and environmental medicine. 06/2014; 71 Suppl 1:A42.
[Show abstract][Hide abstract] ABSTRACT: The association between benzene exposure and non-Hodgkin lymphoma (NHL) has been the subject of debate, and an IARC working group recently concluded for the first time that there is now limited evidence to support this association in humans. We evaluated the relationship between occupational benzene exposure and NHL risk among 73 087 women in a population-based cohort study of women in Shanghai.
Occupational and environmental medicine. 06/2014; 71 Suppl 1:A40-1.