Population Architecture using Genomics and Epidemiology - Women's Health Initiative Clinical Trial and Observational Study

This substudy phs000227 PAGE WHI contains genotypes generated using BeadXpress and Metabochip, produced as part of NHGRI's PAGE project. 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.

WHI
The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer and osteoporotic fractures in postmenopausal women. These chronic diseases are the major causes of death, disability and frailty in older women of all races and socioeconomic backgrounds.

This cohort is sponsored by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), involves 161,808 women aged 50-79, and is one of the most definitive, far-reaching clinical trials of post-menopausal women's health ever undertaken in the U.S. Women were recruited between 1993 to 1998 at 40 centers across the US and follow up is planned to continue until at least 2015. The WHI Clinical Trial and Observational Study focused on many of the inequities in women's health research and will continue to provide practical information to women and their physicians about hormone therapy, dietary patterns, calcium/vitamin D supplementation, and their effects on the prevention of heart disease, cancer and osteoporotic fractures.

The WHI has two major parts: a randomized Clinical Trial and an Observational Study. The randomized controlled Clinical Trial (CT) enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are:

• Hormone Therapy Trials (HT): This component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component took hormone pills or a placebo (inactive pill) until the Estrogen plus Progestin and Estrogen Alone trials were stopped early in July 2002 and March 2004, respectively. All HT participants continued to be followed without intervention until close-out.
• Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants followed either their usual eating pattern or a low-fat dietary pattern.
• Calcium/Vitamin D Trial (CaD): This component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component took calcium and vitamin D pills or a placebo.

The Observational Study (OS) is examining the relationship between lifestyle, health and risk factors and specific disease outcomes. This component involves tracking the medical history and health habits of 93,676 women.

To fully examine the profile of gene and environment interaction, or "epidemiologic architecture," we will comprehensively evaluate such putative genuine variants in the Women's Health Initiative This large study population not only enables us to examine the population incidence for racial and ethnic subgroups and associated risks of rigorously defined, incident diseases (specific aim 1) but allows us to investigate associated risks given in-depth information on various environmental exposures and disease risk factors as well as three randomized interventions (hormone therapy; low-fat dietary modification; calcium + vitamin D supplements) (specific aim 2). The prospective and longitudinal collection of biospecimens, intermediate outcomes, and phenotypic characteristics, such as bone mineral density, hormone concentrations, breast density, or inflammation will further permit us to link genetic variants to relevant intermediate phenotypes, which will potentially provide important clues to the biological basis of the genuine associations (specific aim 3). For a variety of outcomes we will genotype within this 4-year project 72,000 participants for disease-specific putative genuine variants. Information generated from this study will be critical to determine the health impact of any given undisputable variant. Findings may also provide valuable insights into disease pathways and mechanisms, and targets for disease screening, prevention, and treatment.

This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

• Study Weblinks:
  • WHI
  • NHLBI WHI
  • Population Architecture using Genomics and Epidemiology (PAGE)
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Cohort
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 45707
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH
• PMC

Inclusion criteria: Postmenopausal women, aged 50 to 79, who were able and willing to provide written informed consent and who expected to reside in the study recruitment area for at least 3 years following enrollment were eligible.

Exclusion criteria: Study subjects were excluded from the WHI CT and OS if they had medical conditions predictive of a survival time of less than 3 years; if they were known to have conditions that might affect study participation and adherence (alcoholism, drug dependency, mental illness, dementia); or if they were active participants in another randomized controlled clinical trial. In addition, each CT component incorporated specific exclusionary criteria.

WHI Time Line

• October 1992 - Clinical Coordinating Center operations begin
• March 1993 - 16 Clinical Centers selected
• September 1993 - Recruitment of participants for 2 Hormone Therapy Trials (HT) trials and the Dietary Modification Trial (DM) begins
• September 1994 - 24 additional Clinical Centers selected; Recruitment of participants for the Observational Study (OS) begins
• June 1995 - CaD randomization begins
• August 1998 - Randomization of participants for the DM ends
• October 1998 - Randomization of participants for the HT ends
• December 1998 - Recruitment of participants for the OS ends
• September 2000 - Randomization of participants for the CaD ends
• July 2002 - Estrogen plus Progestin HT was stopped early and main results published
• March 2004 - Estrogen-Alone HT was stopped early
• April 2004 - Main results of Estrogen-Alone HT published; Closeout of OS begins
• October 2004 - Closeout of clinical trials (HT, DM, and CaD) begins
• March 2005 - Study close-out ends
• April 2005 - Extension study begins
• September 2005 - Final WHI outcomes obtained and WHI database closed
• February 2006 - Main results of DM and CaD published
• September 2011 - Extension study continued

• Primary Phenotype: Women's Health
• Type 2 Diabetes Mellitus
• Obesity
• Cholesterol, HDL
• Cholesterol, LDL
• Coronary Disease
• Triglycerides
• Myocardial Infarction
• Inflammation
• Stroke

• Principal Investigators
  • Charles Kooperberg. Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Ulrike Peters. Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
• Institute
  • National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
• Funding Source - Genotyping and Analysis
  • U01HG007376. National Institutes of Health, Bethesda, MD, USA.
  • U01HG004790. National Institutes of Health, Bethesda, MD, USA.
• Funding Sources
  • N01WH22110. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH32100-2. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 24152. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 32105-6. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 32108-9. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 32111-13. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 32115. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 32118-32119. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 32122. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 42107-26. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 42129-32. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • N01WH 44221. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • HHSN268201100046C. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.