Nutritional Epidemiology

Cancer risk reduction and diet: A cohort study of women 
PI:  Zheng, Wei      Funding Agency:  NCI     Grant No.:  R37 CA070867 
Description: Using data and biological samples collected from the Shanghai Women’s Health Study (SWHS), we are evaluating several important etiologic hypotheses for cancer that are difficult to investigate in other existing cohort studies. We are studying dietary factors that could potentially reduce the risk of cancer. We also conduct nested case-control studies to evaluate biomarkers that could potentially be used for cancer risk prediction and assessment.

Consortium Study of Modifiable Causes of Death in Asians
PI:  Zheng, WeiPotter, John       Funding Agency: NCI      Grant No.:  R03 CA153116 
 Description: In Asian countries, in the wake of lifestyle changes (reduced physical activity, increased prevalence of obesity and cigarette smoking, and heavy alcohol consumption), the burden of chronic diseases has increased substantially in recent decades. Each of these modifiable factors has been linked to premature death; however, the overall impact of these factors on total and cause-specific mortality is unclear. This study will also evaluate the association of central obesity with total and cause-specific mortality. This study is being conducted as part of the Asia Cohort Consortium, in which data from more than 1 million individuals recruited in approximately 20 cohort studies have been harmonized and analyzed to quantify the association of BMI and tobacco smoking with total and cause-specific mortality (Zheng W, et al, NEJM, 2011; 364(8):719-29; Zheng W, et al, PLoS Medicine, 2014; 11(4):e1001631). Study results will inform the design of effective programs tackling the emerging epidemic of chronic diseases and reduce premature death in Asian countries.

Effect of magnesium treatment on vitamin D resistance 
PI:  Shrubsole, Martha       Funding Agency:  NCI         Grant No.:  R03 CA189455 
 Description:  Despite fortification or supplementation and even adequate sunlight exposure, vitamin D insufficiency or deficiency is still relatively common in the US.  One striking observation is that a large portion of the inter-person variation in serum 25-hydroxyvitamin D (25(OH)D) levels is unexplained. Magnesium (Mg), the second most abundant intracellular cation, plays a critical role in the synthesis and metabolism of vitamin D. Previous in vitro studies have indicated that the activities of three major enzymes determining 25(OH)D level may be Mg-dependent. We are evaluating whether Mg supplementation affects serum 24,25(OH)D and the ratio of 24,25(OH)D/ 25(OH)D, and, thus, improves vitamin D resistance (i.e. insensitivity to vitamin D supplementation) and reduces risks of diseases related to vitamin D deficiency/resistance (e.g. colorectal cancer) using data and serum samples collected in the Personalized Prevention of Colorectal Cancer Trial, a randomized controlled intervention trial of Mg supplementation.


Fatty acid desaturase activity, fish oil and colorectal cancer chemoprevention 
PI: Murff, Harvey       Funding Agency: NCI           Grant No.: R01 CA160938 
Description: Observational studies have suggested that the n-3 polyunsaturated fatty acids, eicosapentanoic acid and docosahexanoic acid, may reduce the risk of colorectal cancer. Our hypothesis is that individuals with lower activity of fatty acid desaturase-1(FADS1) will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity due to lower production of endogenous arachidonic acid. To test this hypothesis we will recruit 150 participants and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our specific aims include: 1) to determine the efficacy of fish oil supplements on rectal epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil supplementation for colorectal cancer chemoprevention.

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Fogarty International Clinical Research Scholars Support Center @ Vanderbilt-AAMC (FICRSF)
PI: Vermund, Sten       Funding Agency:  FIC          Grant No.:  R24 TW007988 
Description: The goal of the program is to help train and inspire both US and foreign graduate students in research techniques and topic areas applicable to resource-limited and/or tropical countries.

Genetic and Endocrine Pathways Linking Obesity to Prostate Cancer  
PI: Fowke, Jay H.       Funding Agency:  NCI             Grant No.: R01 CA121060 
Description: The purpose of this study is to investigate the associations between obesity, prostate cancer, and high-grade prostatic intraepithelial neoplasia (PIN). Toward this goal, we developed a multi-centered rapid-recruitment protocol targeting men seeking a diagnostic prostate biopsy within any urology clinic in metro Nashville, TN.  Trained staff measure body size and body composition using bioelectric impedance analysis, collect pre-diagnosis blood and urine for biomarker and genetic analyses, administer a research lifestyle questionnaire, and perform medical chart review for clinical and pathology data.  Genetic and molecular markers of obesity are investigated toward prostate cancer and PIN risk.

Long-chain fatty acids, oxidative stress and colorectal neoplasm risk 
PI: Murff, Harvey       Funding Agency: NCI       Grant No.: R01 CA143288 
Description: Chronic inflammation is contributors to colorectal carcinogenesis. Eicosapentanoic acid exhibits anti- inflammatory actions while arachidonic acid, an omega-6 polyunsaturated fatty acid, appears pro- inflammatory. Our overarching hypothesis is that individuals with increased dietary ratios of arachidonic acid to eicosapentanoic acid will have an increased risk of colorectal adenoma and that this increased risk is mediated through pro-inflammatory eicosanoids and increased oxidative stress. The specific aims of this research proposal are: 1) To test the hypothesis that a greater erythrocyte phospholipid membrane arachidonic acid to eicosapentanoic acid ratio is associated with an increased risk of colorectal adenomas; 2) To test the hypothesis that an increase in urinary levels of F2-isoprostanes is associated with an increase risk of colorectal adenomas and; 3) To test the hypothesis that a greater arachidonic acid to eicosapentanoic acid ratio is associated with increased levels of prostaglandin E2 and urinary F2-isoprostanes.

Methionine Metabosism in Esophageal Adenocarcinoma Carcinogenesis 
PI: Shrubsole, Martha          Funding Agency:  NCI           Grant No.: R03 CA195660 
Esophageal adenocarcinoma (EA) incidence in the western world has rapidly increased but survival remains low. Most EA arises in Barrett’s Esophagus (BE) although the etiology of both diseases are poorly understood and there are very few known modifiable risk factors. Recent studies suggest DNA hypomethylation may be a key factor that appears early in carcinogenesis. The methyl donor S-adenosylmethionine (SAM) from the methionine cycle is involved in both one-carbon metabolism (OCM) and DNA methylation. We previously found higher plasma SAM levels were associated with decreased neoplasia risk in two studies. We also found dietary OCM factors have a role in BE and EA risk. Thus, we are testing the hypothesis that methionine cycle metabolism has a role in EA carcinogenesis in a study using plasma samples from a population-based case-control study of BE and EA based in Northern Ireland.

Nashville Breast Health Study
PI:  Zheng, Wei         Funding Agency: NCI          Grant No.: R01 CA100374 
This study is a population-based, case-control study of breast cancer conducted in Nashville, Tennessee since 2004. Its primary aim is to study genetic factors and gene-environment interactions in relation to breast cancer risk. Approximately 6,000 breast cancer cases and controls have been recruited; the vast majority of participants provided an exfoliated buccal cell or saliva sample as a source of genomic DNA. Breast tumor tissue samples have been collected from approximately 1400 participants with breast cancer. The main study ended in 2010. However, recruitment for breast cancer patients of African ancestry has been continued and expanded to other regions, including greater Tennessee, South Carolina and Georgia. Data and biological samples collected in this study have been used in multiple projects, including the first genome-wide association study of breast cancer in African Americans.

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Obesity, Inflammation, and BPH 
PI: Fowke, Jay H.       Funding Agency: NIDDK            Grant No.: R01 DK087962 
Description: The purpose of the study is to investigate the relationship between obesity and BPH.  Obesity generates a state of chronic systemic inflammation known to enhance arthrosclerosis, diabetes, and other inflammatory diseases. Several studies also suggest that obese men are also more likely to develop lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).  However, much of the epidemiologic evidence relies on self-reported BPH outcomes, and there are few, if any, animal models to characterize the obesity-BPH relationship. Thus, our long-term goals are to characterize the relationship between obesity and prostate tissue inflammation and hyperplasia, investigate potential mechanisms by which obesity advances BPH, develop a mouse model of BPH for mechanistic studies, and to conduct a prospective epidemiologic study to investigate the clinical impact of obesity on BPH progression.

O’Brien Center Development: BPH and Obesity 
PI: Fowke, Jay H.       Funding Agency:  NIDDK           Grant No.: P20 DK097782 
Description: This is toward development of a Center to investigate obesity and BPH.  we conduct two epidemiologic investigations to determine if prostate tissue inflammation or LUTS severity is associated with hypothesized pathways linking obesity to BPH, including increased PGE-M (inflammation), F2-isoprostanes (oxidative stress), and adiponectin and C-peptide (insulin activity).

Polyunsaturated Fatty Acids and Colorectal Tumor Risk: A Molecular and Genetic Epidemiology Study
PI: Khankari, Nikhil                      Funding Agency: NCI         Grant No.: K99 CA215360
Description: Arachidonic acid, a long-chain ω-6 polyunsaturated fatty acid (PUFA), has been demonstrated to affect carcinogenesis in animal and in vitro studies. The effect of arachidonic acid is believed to be largely due to overproduction of the eicosanoid, prostaglandin E2 (PGE2). The other class of PUFAs, ω-3, also bind to the same enzymes involved in arachidonic acid metabolism; however, the resulting set of eicosanoids are anti-inflammatory. Thus, ω-3 PUFA metabolism could indirectly inhibit PGE2 production and reduce cancer risk. Over the past few years, multiple genetic variants have been identified to be associated with PUFAs. The goal of this study is to elucidate the potential causal association between long-chain PUFAs and colorectal tumor risk using Mendelian randomization (MR), an approach that may avoid potential pitfalls of conventional observational epidemiologic research and utilizes genetic variation as a proxy for exposures

Shanghai Breast Cancer Study (SBCS)
PI: Zheng, Wei, Shu, Xiao Ou     Funding Agency:  NCI   Grant No.: R01 CA090899,R01 CA064277 
Description: The Shanghai Breast Cancer Study (SBCS) is a population-based, case-control study funded by NCI since 1996 to investigate lifestyle factors, genetic susceptibility, and other biomarkers associated with breast cancer risk and survival. Included in the study are approximately 3,500 breast cancer cases aged between 25 and 70 years and an equal number of community controls recruited among female residents of Shanghai, China. In addition to in-person interview data, biological samples were collected from study participants. The resources from the study have supported multiple research and training grants and provided opportunities for many graduate students and postdoctoral fellows to conduct research. To date, over 150 research papers have been published from the SBCS addressing a wide range of significant issues related to dietary, lifestyle, environmental, and genetic contributions to breast cancer risk and prognosis.

Shanghai Endometrial Cancer Study (SECS) 
PI: Shu, Xiao Ou          Funding Agency:  NCI           Grant No.:  R01 CA092585 
Description: The Shanghai Endometrial Cancer Study is a population-based, case-control study of 1,204 endometrial cancer cases and 1,212 controls who were aged between 30 and 69 years and recruited between 1997 and 2003. The study recently recruited an additional 587 endometrial cancer patients. The major objectives of the study are to evaluate the role of and interactions between hormonal, dietary, and other lifestyle factors and genetic susceptibility in endometrial carcinogenesis. In addition to detailed dietary intake and other questionnaire-based information, the study also collected a blood or buccal cell sample and a urine sample from participants. The study has published multiple papers reporting novel findings on dietary risk/protective factors and genetic susceptibility factors. The SECS is one of the largest epidemiological studies of endometrial cancer and is a major contributor to the international Epidemiology of Endometrial Cancer Consortium.

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Shanghai Men’s Health Study (SMHS) 
PI: Shu, Xiao Ou            Funding Agency:  NCI        Grant No.: R01 CA82729, UM1 CA173640 
Description: The Shanghai Men’s Health Study (SMHS), funded by NCI since 2001, is a population-based cohort study of 61,482 men aged between 35 and 75 years and recruited from 2002 to 2006. At baseline, detailed information on dietary intakes, personal habits, occupational history, medical history, and other lifestyle factors was collected, and anthropometrics were measured. Blood or buccal cell, and  urine samples were collected from 89% of participants. The cohort has been followed through multiple in-person surveys to update exposure information and through record linkages with the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Registry to obtain information on cancer occurrence and survival status. Over the years, SMHS data and biological samples have been used to evaluate many important etiologic hypotheses addressing the contributions of environmental, dietary, lifestyle, and genetic exposures to the development of cancer and other chronic diseases. The cohort supports multiple studies, including over 25 consortium projects.

Shanghai Women's Health Study (SWHS) 
PI: Zheng, Wei          Funding Agency:  NCI           Grant No.: UM1 CA182910 
 Description: This population-based prospective cohort study was initiated in 1996. From 1996 to 2000, approximately 75,000 Chinese women living in Shanghai were recruited into the study. In addition to survey data, most study participants donated blood (75%) and urine (87%) samples at baseline. Approximately 50% of study participants who did not donate a blood sample provided a sample of exfoliated buccal cells. This cohort of women is being followed for incidence of site-specific cancers and cause-specific mortality through a combination of in-person surveys and record linkages with population-based registries. Four in-person follow-up surveys have been completed, each with a response rate greater than 90%. The resources from this study have supported multiple studies, including approximately 40 international research consortia, to address etiologic hypotheses for cancers and other chronic diseases. The SWHS, with its large sample size, wealth of resources, and unique exposure patterns and disease spectrum, provides exceptional opportunities to address many significant hypotheses that cannot be adequately investigated in other existing cohorts.

Tennessee Colorectal Polyp Study 
PI: Zheng, WeiReid Ness         Funding Agency:  NCI         Grant No.: P50 CA90949 
Description:  This project was conducted as part of the Vanderbilt SPORE in GI Cancer (PI, Robert Coffey). Recruitment for this study ended in 2010; however, data and biological samples collected in this study continue to be used in multiple studies. The primary aim of this study is to evaluate lifestyle factors and biomarkers for the risk and recurrence of colorectal polyps. Participants were recruited from patients who were scheduled for clinically-indicated colonoscopy at the VU Hospital and the VA Tennessee Valley Healthcare System. More than 7,000 patients were recruited and completed a telephone interview. Biological samples, including blood, exfoliated buccal cells, polyp tissues, and rectal biopsies, were collected from eligible subjects. The resources from this project have supported multiple externally-funded studies, including three K07 grants for career development of junior investigators and multiple R01-funded studies. 

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Vanderbilt-Emory-Cornell-Duke Consortium for Global Health Fellows (VECDor) 
PI: Vermund, StenHeimburger, Douglas         Funding Agency:  FIC    Grant No.: R25 TW009337 
Description: This project aims to nurture a new generation of global health researchers through a collaborative training program with overseas research institutions from low and middle-income countries with which our universities have worked for decades.