Integrative genomics and risk of CHD and related phenotypes in the Women's Health Initiative

This substudy phs001335 Integrative genomics and risk of CHD and related phenotypes in WHI study was to analyze epigenetic markers in blood and to associate these markers with phenotypes related to coronary heart disease. Summary level phenotypes for the WHI Cohort study participants can be viewed at the top-level study page phs000200 WHI Cohort. Individual level phenotype data and molecular data for all WHI top-level study and substudies are available by requesting Authorized Access to the WHI Cohort study phs000200.

In 2013, three contracts were awarded in response to the federal contract opportunity entitled "Towards Maximizing the Scientific Return on the Women's Health Initiative Biological Resource" (NHLBI-CSB-WH-13-01-ST) for research and development in the physical, engineering, and life sciences (except biotechnology) at National Institutes of Health National Heart, Lung and Blood Institute, Rockledge Dr. Bethesda, MD. Supporting documentation for this RFP and a list of contract winners can be found here https://govtribe.com/project/towards-maximizing-the-scientific-return-on-the-womens-health-initiative-biological-resource-1

The focus of this contract (HHSN268201300006C) entitled "Integrative genomics for risk of CHD and related phenotypes in the Women's Health Initiative" and awarded to Stanford University was to apply validated high throughput genomic procedures developed by Applied Biosystems and Illumina to the plasma and DNA samples of a subset of WHI participants with existing GWAS and CVD biomarker data. The study funded by this contract is also known as BA23 (the 23rd Broad Agency contract awarded to the WHI study). The original aims of this proposal was to generate these data to allow the BA23 investigators and others 1) to identify genomic biomarkers of CHD events, 2) to integrate these biomarkers into diagnostic and prognostic predictors of CHD and related phenotypes, 3) to elucidate the biology of CHD and related phenotypes, 4) to test whether aging related CpGs mediate the risk of age on CHD, and 5) to revisit the GWAS studies of CHD using new SNP set analysis informed by these new genomic data to uncover novel SNPs, genes, and pathways involved in CHD as well as novel molecularly refined CHD sub phenotypes.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• Total number of consented subjects: 2129
• Subject Sample Telemetry Report (SSTR)

The original sampling design proposed was a pseudo case-cohort sampling of WHI participants with the random cohort being sampled from baseline (enrollment into WHI CT or OS between 1993-98) stratified by race/ethnicity with a ~2:1:1 ratio of European, African American, and Hispanic women. The total number of subjects using this design was expected to be ~2140 with ~half of these subjects being non-cases and half being subjects with adjudicated incident coronary heart disease event during follow up (cases). We use the term pseudo case-cohort because there were several caveats to this sampling design that would not allow for a clean case-cohort sampling including the need to restrict the sample to participants who were dbGaP eligible by having signed supplemental consent in 2005 and the desire to preferentially select samples that already had CVD biomarker measures at baseline as well as GWAS. We note that women who died prior to 2005 and never had an opportunity to sign supplemental consent in 2005 had been previously deemed dbGaP eligible and could be sampled here. Approximately 92-94% of the entire WHI cohort ended up being dbGaP eligible.

This original sampling design was modified post-award to accommodate a request from the NHLBI to maximize the overlap of the number of samples being profiled with different "omic" technologies by the three investigative teams that were funded through this contract opportunity. The new sampling design led to one case-control and one pseudo case-cohort sample set for this study. Cases were defined by the first incident centrally adjudicated angina, revascularization, or CHD event, as of the September 17, 2012 version of the WHI database. Eligible participants satisfied the following criteria: 1) European American, African America, and Hispanic women with no self-report of CVD at baseline, 2) have biomarkers measured in the HT CVD biomarker study, core study or W54/58, 3) met these sample requirements, 4) had GWAS data (when available) from W63, SHARe, GARNET, GECCO, or BA3.

The case-control samples set includes a total of 637 cases and 631 controls which can be divided into a set of 145 cases and 145 control that overlap with both of the other two contracts and a set of 489 cases and 489 controls overlapping with one of the other two contracts. The pseudo case-cohort sample includes 472 cases and 432 controls.

• Primary Phenotype: Coronary Artery Disease
• Cholesterol
• Insulin
• Blood Glucose
• Type 2 Diabetes
• C-Reactive Protein
• Blood Pressure
• Aging
• Smoking
• Body Mass Index

• Co-Principal Investigators
  • Devin Absher. HudsonAlpha Institute of Biotechnology, Huntsville, AL, USA.
  • Themistocles Assimes, MD, PhD. Stanford University School of Medicine, Stanford, CA, USA.
  • Steve Horvath, PhD. University of California Los Angeles, Los Angeles, CA, USA.
  • Phil Tsao, PhD. Stanford University School of Medicine, Stanford, CA, USA.
• Funding Sources
  • HHSN268201300006C. National Institutes of Health, Bethesda, MD, USA.