Molecular and Genomic Epidemiology

Wei Zheng, Chris Haiman (University of Southern California)  Julie Palmer (Boston University)     
Funding Agency: NCI      
Grant Number:  R01CA202981 

The age-adjusted breast cancer mortality rate is more than 40% higher in African Americans than in whites for reasons poorly understood. To date, genome-wide association studies (GWAS) are mostly conducted in Asian and European descendants. However, only a few of the GWAS-identified risk variants can be directly replicated in African-ancestry women. GWAS are often not equipped to study structural variants and are inefficient for capturing low-frequency variants. These variants, although not yet adequately investigated, may contribute substantially to the heritability of breast cancer. In this consortium, we will generate new genomic data using whole genome sequencing and high-density genotyping arrays and consolidate GWAS data from existing studies to search genetic risk variants for breast cancer. Furthermore, we will evaluate how germline risk variants identified in this study and previous studies affect the major signaling pathways of breast cancer. More than 40,000 breast cancer patients and controls of African descent recruited from >20 studies conducted in the US and Africa will be included in this study. 

Wei Zheng, Jirong Long
Funding Agency: NCI       
Grant Number: R01CA188214

Known genetic factors explain only a small fraction of colorectal cancer (CRC) heritability. This study expands our ongoing genome-wide association study (GWAS) in East Asians, the Asia Colorectal Cancer Consortium (including approximately 250,000 cases and controls), to identify new genetic susceptibility loci for CRC. We use fine-mapping and in vitro and in vivo functional analyses to discover functional variants and genes that drive the associations. The results of this study should help accelerate the translation of GWAS findings into disease prevention and treatment.

Loren Lipworth, Immaculata De Vivo, Wendy Setiawan  Margaret Du
Funding Agency: NCI 
Grant Number: R01CA250476

Endometrial cancer is becoming increasingly common, particularly in women with aggressive tumors who have poor outcomes. African American women have higher mortality than other racial/ethnic groups even after accounting for stage, histology, comorbid conditions, and treatment. Here, we will use the largest, most diverse population to date (including >1,000 African American and >2,000 non-African American endometrial cancer patients) in the Epidemiology of Endometrial Cancer Consortium (E2C2) to investigate endometrial tumor genomics, distinct risk factor profiles across tumor types, and the role of underlying tumor biology in driving this large survival disparity. 

Wei Zheng, Jirong Long
Funding Agency: NIH 
Grant Number: R01CA148677 

This study is comprised of two projects that significantly advance our understanding of the genetic basis for breast cancer and the methodology for genetic epidemiologic research. The first project expands the genome-wide association study (GWAS), the Asia Breast Cancer Consortium we initiated in 2008 (R01 CA124558), to identify novel risk variants for breast cancer using data collected from ~125,000 cases and controls of east Asian ancestry. In the second project, we sequence GWAS-mapped regions with a goal of identifying additional genetic risk variants, particularly low-frequency risk variants, for breast cancer. This is the only well-powered genetic study of its kind conducted in Asian women, and thus offers the opportunity to discover genetic variants for breast cancer that are unlikely or more difficult to identify in GWAS of other populations.

Jirong Long, Fei Ye
Funding Agency: NCI
Grant Number:: R01CA247987

To conduct methylome-wide association study to identify novel genes and methylation loci for breast cancer.

Tina Hartert, MD, MPH, James Gern, MD (consortium PI)
Funding Agency: NCI
Grant Number:: UH3 OD023282

CREW will provide a large (nearly 9000 births and long-term follow-up of 6000-7000 children and young adults) and diverse national dataset that will be optimized for systems analysis of early life exposures and events that influence asthma endotypes. The study goals are to establish how environmental and host factors in early life promote the development of specific asthma endotypes.

Wei Zheng
Funding Agency: NIH
Grant Number:  R01 CA158473 

Known genetic risk factors explain about 28% of breast cancer heritability. Emerging evidence strongly suggests that a large fraction of the heritable risk for breast cancer and other complex diseases may be difficult to identify using conventional methods and genome-wide association studies (GWAS). This study systematically searches the entire coding region in the human genome to identify new genetic susceptibility factors for breast cancer. This is the first large association study for breast cancer using whole exome sequencing. It is anticipated that this study will identify novel genes and pathways to significantly improve our understanding of breast cancer genetics and biology. 

Danxia Yu
Agency: NHLBI
Grant Number: R01HL149779 

To identify circulating gut microbial metabolites related to the risk of incident coronary heart disease among Chinese, White Americans, and African Americans.

Tina Hartert
Funding Agency: NIH/NIAID 
Grant Number: U19 AI 095227 

Twelve city SARS-CoV-2 surveillance study of household units to understand immune response, transmission, symptomatology and role of asthma and allergies in infection. 

Qiuyin Cai, Jirong Long
Funding Agency: NIH/NCI     
Grant Number: R01 CA249863 

To systematically integrate transcriptome, methylome, and genome data to identify novel genes and methylation loci for lung cancer risk.

Qiuyin Cai, Jirong Long
Funding Agency: NIMHD    
Grant Number:  R01MD015396

To investigate how individual and social contextual factors might affect DNA methylation and biological aging in racial minorities and identify potential mechanisms by which individual and social contextual factors might affect lung cancer risk in AAs and low SES EAs.

Wei Zheng, Jirong Long
Funding Agency: NCI
Grant Number: R01CA235553 

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) correlating to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in most GWAS-identified loci are unknown. Furthermore, a large part of breast cancer heritability remains unexplained. We propose a well-powered transcriptome-wide association study (TWAS) to systematically search the whole transcriptome to identify genes associated with breast cancer risk using data from approximately 320,000 breast cancer patients and controls. We will also perform in vitro assays to functionally characterize promising genes identified in TWAS. Finally, we will evaluate whether TWAS-identified genes may contribute to racial differences in breast cancer risk by molecular subtypes. 

Christianne Roumie, Carlos G. Grijalva
Funding Agency: AHRQ
Grant Number: 1T32HS026122

This training program provides support for personalized mentoring for projects related to the learning healthcare system paradigm.

PIs: Wang, Thomas, Shu, Xiao-Ou, Gerzten, Robert (Harvard University)
Agency: NIH/NIDDK
Grant No.: R01DK108159-01A1

Type 2 diabetes mellitus (DM) is a major cause of morbidity and mortality worldwide. The pathogenesis of DM reflects a complex interplay of genetic, dietary, and environmental exposures affecting multiple pathways. It is well recognized that there is phenotypic heterogeneity among individuals who develop DM. Using resources from the Shanghai Women's Health Study and Shanghai Men's Health Study, this study comprehensively evaluates metabolomic profiling to identify metabolites associated with incident DM in a population with low prevalence of obesity. This research applied a two-phase nested case-control study design and included metabolomic data from a total of 2,258 participants. (Research activities are ongoing.)

Wei Zheng
Funding Agency: NCI          
Grant Number: R01CA100374

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 and most participants provided an exfoliated buccal cell or saliva sample as a source of genomic DNA. Breast tumor tissue samples have been collected from approximately 1,400 participants with breast cancer. The main study ended in 2010. However, we continue to use data and biological samples collected in this study for multiple projects, including the first genome-wide association study of breast cancer in African American women.

Qiuyin Cai, Lynn Rosenberg
Funding Agency: NIH/NCI
Grant Number:  R01 CA207466 

To investigate whether oral microbiome may be associated with lung cancer risk among African Americans and European Americans.

Jose Florez (Mass General)
Agency: NHLBI
Grant Number: R01DK123019

This study will validate GWAS findings regarding the association of genetic factors with glycemic response to pharmacotherapy for Type 2 diabetes (T2DM).

Nikhil Khankari
Agency: NIH/NCI
Grant Number: R00CA215360

Arachidonic acid, a long-chain omega-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, omega-3, also bind to the same enzymes involved in arachidonic acid metabolism; however, the resulting set of eicosanoids are anti-inflammatory. Thus, omega-3 PUFA metabolism could indirectly inhibit PGE2 production and reduce cancer risk. Multiple genetic variants have been identified to be associated with PUFAs. The goal of the proposed K99/R00 award 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.

Wei Zheng
Funding Agency: NIH
Grant Number: R01CA64277, RO1CA090899

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 between the ages of 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. 

Xiao-Ou Shu
Funding Agency: NIH/NCI
Grant Number: DAMD 17-02-1-0607, R01 CA118229

The Shanghai Breast Cancer Survival Study (SBCSS) is a population-based cohort study of 5,042 women who were diagnosed with primary breast cancer between ages 25 and 74 years. Participants were identified from the population-based Shanghai Cancer Registry and recruited to the study approximately 6 months after cancer diagnosis between April 1, 2002 and December 31, 2006 (response rate: 80.1%). The study has completed multiple in-person interviews administered at 6, 18, 36, and 60 months after diagnosis, which collected information on cancer diagnosis, treatment, progression, lifestyle factors, and quality of life. The 10-year post-diagnosis survey is ongoing. Medical charts were abstracted to verify cancer diagnosis and initial treatments; tumor slides were collected. The vast majority of study participants (96%) provided DNA samples to the study. The SBCSS has published many high impact papers addressing the influences of lifestyle, psychosocial, and genetic factors on cancer outcomes and quality of life among survivors. (Research activities are ongoing.)

Xiao-Ou Shu
Funding Agency: NCI
Grant Number: R01 CA092585

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 major objectives of the study are to evaluate the roles 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. (Research activities are ongoing.)

Wei Zheng
Funding Agency: NIH
Grant Number: UM1CA182910

This population-based prospective cohort study was initiated in 1996, in which ~75,000 Chinese women living in Shanghai were recruited from 1996 to 2000. In addition to survey data, most study participants donated a blood or mouthwash sample and a urine sample at baseline. This cohort of women is being followed for incidence of site-specific cancers and cause-specific mortality. Five in-person follow-up surveys have been completed, each with a response rate greater than 90%. The resources from this study have supported more than 200 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, unique exposure patterns, and disease spectrum, provides exceptional opportunities to address many significant hypotheses that cannot be adequately investigated in other existing cohorts.

Wei Zheng, Wen Wanqing
Funding Agency: NIH
Grant Number: UM1CA182910

This population-based prospective cohort study was initiated in 1996, in which ~75,000 Chinese women living in Shanghai were recruited from 1996 to 2000. In addition to survey data, most study participants donated a blood or mouthwash sample and a urine sample at baseline. This cohort of women is being followed for incidence of site-specific cancers and cause-specific mortality. Five in-person follow-up surveys have been completed, each with a response rate greater than 90%. The resources from this study have supported more than 200 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, unique exposure patterns, and disease spectrum, provides exceptional opportunities to address many significant hypotheses that cannot be adequately investigated in other existing cohorts.

Song Yao (Roswll Park Cancer Institute), Wei Zheng (VUMC)  John Carpten (USC)  Julie Palmer (Boston University)
Funding Agency: NIH
Grant Number: R01CA228156 

Women of African ancestry are disproportionately afflicted with triple-negative breast cancer (TNBC), and bear the highest mortality rate of all populations from the disease in the U.S. In this research consortium, we propose to characterize the mutational landscape of TNBC in African American women by performing whole-exome sequencing and RNA-sequencing. We will then compare significantly mutated genes and mutational signatures between African- and European-ancestry women. Finally, we will investigate genetic and environmental factors in relation to somatic mutations. This research will greatly advance the field of breast cancer research by characterizing the tumor mutational landscape in African American women and determine whether cancer biology at the somatic mutation level differs by ancestral populations. 

Wei Zheng, Martha Shrubsole
Agency: NIH
Grant Number: U01CA202979 

The SCCS was initiated in 2001. Nearly 86,000 adults aged 40-79 at cohort entry were recruited during 2002-2009 across 12 southern states, mostly at Community Health Centers (institutions providing basic health and preventive services in underserved areas). By design, two-thirds of the cohort was selected to be African American and the remainder predominantly non-Hispanic white to help remedy the underrepresentation of African Americans in health studies and enable direct black/white comparisons. Most of the cohort members, both black and white, had low income and education levels. In addition to detailed survey data, biospecimens were collected from more than 76,000 cohort members at baseline, with blood obtained and stored for approximately 39,000, mouth rinses/saliva for 38,000, and urine for 24,000, so that genomic DNA could be extracted from nearly 90% of participants. In 2018, we initiated stool sample collection and have collected these samples from ~8,500 cohort members. This cohort is being followed for incidence of site-specific cancers and cause-specific mortality. Data and biospecimens collected in the SCCS have been used to support large numbers of epidemiologic and genetic studies of cancer and other chronic diseases. 

Wei Zheng, Harvey Murf
Funding Agency:  NIH
Grant Number: P50CA095103 

 This project was conducted as part of the Vanderbilt SPORE in GI Cancer (PI, Robert Coffey).  Most colorectal cancers arise from adenomatous polyps, and a large proportion of adenoma patients develop new (metachronous) adenomas after their initial polypectomy. 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 VUMC 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. Recruitment for this study ended in 2010; however, data and biological samples collected in this study continue to be used in multiple studies. The resources from this project have supported multiple externally funded studies, including six K07 or K99/R00 grants for career development of junior investigators and multiple R01-funded studies.

Danxia Yu
Funding Agency:  NIDDK
Grant Number: R01DK126721 

To establish a longitudinal cohort of patients undergoing metabolic surgery, examine changes in the gut microbiome and microbial metabolites, and identify microbial features that may predict cardiometabolic improvements after surgery.

Danxia Yu
Funding Agency:  NHLBI
R21HL140375 

We conducted an international consortium-based analysis of circulating TMAO and related metabolites in relation to dietary intakes and cardiometabolic biomarkers. A total of 17 cohort studies from the US, Europe, and Asia participated in this pooling project.

Wei Zheng
Funding Agency:  NIH
Grant Number: R01CA097386

This study officially ended in 2008, but the resources it established continue to be used to support other studies. The aim of this study was to study biomarkers that can be used to predict adenoma recurrence after initial polypectomy. Approximately 1,200 patients with either an advanced adenoma or multiple adenomas were recruited from Tennessee and Indiana. Polyp tissue samples from these patients have been used to evaluate multiple tumor markers.

Wilbroad Mutale, MBChB, PhD, Douglas C Heimburger, MD, MS
Funding Agency: NIH
Grant Number: 5D43 TW009744

UVP trains Zambian PhD- and postdoctoral HIV researchers, equipping them with research skills in non-communicable complications and comorbidities of HIV, while expanding the University of Zambia (UNZA) / University Teaching Hospital's (UTH) research training and investigative capacities.

Xiao-Ou Shu, Setiawan, Veronica (USC)
Funding Agency:  NCI
Grant Number: R01 CA227133

Detecting pancreatic cancer at an early, asymptomatic stage is a top priority for reducing incidence and mortality of this most fatal disease. This multi-center study utilizes pre-diagnostic blood samples collected in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, Southern Community Cohort Study (SCCS), Multiethnic Cohort Study (MEC), Shanghai Women's Health Study (SWHS), and Shanghai Men's Health Study (SMHS) to discover and validate circulating microRNAs as biomarkers for pancreatic cancer early detection and risk assessment. (Research activities are ongoing.)

Xiao-Ou Shu
Funding Agency: NCI            
Grant Number: T32 CA160056

This NCI-funded training program is designed to build an elite class of epidemiologists to lead multidisciplinary collaborative research in cancer. The program delivers individualized didactic and research training to equip postdoctoral fellows from a variety of disciplines with the methodological tools, practical laboratory and survey-research knowledge, and hands-on research and grant writing experience necessary to launch independent careers in the molecular and genetic epidemiology of cancer. For more information, please visit: https://www.vumc.org/magec/welcome. (Research activities are ongoing.)

Tina Hartert, MD, MPH, Stokes Peebles, MD
Funding Agency: NIH/NIAID
Grant Number: U19 AI 095227

We will use a combination of human natural quasi-randomization studies of infant RSV infection specifically designed to assess the impact of infant RSV infection on subsequent respiratory health and the airway epithelium, and in vitro models of RSV infection of nasal airway epithelial cells (NAECs). The overarching objectives of the 3 aims that will test these hypotheses are: 1) to determine whether the age of first infant RSV infection is associated with risk of subsequent incident recurrent wheeze and asthma; 2) to delineate the longitudinal effects of RSV on airway epithelial cell differentiation and metabolism throughout infancy and childhood; 3) to evaluate host gene  infant RSV infection interactions and RSV-dependent NAEC DNAm longitudinally to identify changes and temporal stability of RSV-dependent DNAm marks and their association with recurrent wheeze and asthma.