Cholesterol and Pharmacogenetics (CAP) Study

The Cholesterol and Pharmacogenetics Study was a 6-week open label, non-randomized study of 40mg/day simvastatin treatment in 335 black and 609 white (944 total) men and women. Plasma lipids and lipoproteins were measured on two occasions prior to treatment and at 4 and 6 weeks of treatment. The study was designed to test for genetic associations with baseline measurements and changes in response to simvastatin treatment.

Whole genome genotyping was performed on 592 white CAP study participants in two stages. In Stage 1, 304 were genotyped for 314,621 SNPs to tag for common genomic variation. In Stage 2, 290 participants were genotyped, including 280 who were genotyped for 620,901 SNPs. Two samples were excluded due to gender discrepancies. More recently, CAP self-reported black participants were genotyped on Illumina Omni2.5Exome chips.

PolyA-selected strand-specific RNA-seq libraries were generated in several batches from lymphoblastoid cell lines (LCLs) derived from 268 white and 165 black CAP participants. The LCLs were exposed to sham buffer (control) or 2 uM activated simvastatin for 24 hours, producing a total of 866 100/101 bp paired end RNA-seq libraries sequenced on Illumina HiSeq 2000 machines.

• Study Weblinks:
  • Cholesterol and Pharmacogenetic Study (CAP)
• Study Design:
  • Clinical Trial
• Study Type:
  • Clinical Trial
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 762
• Subject Sample Telemetry Report (SSTR)

• PubMed

Inclusion Criteria:

• at least 30 years of age
• Total cholesterol between 160 to 400 mg/dl
• ≥ 3 black (predominantly African American) grandparents or ≥ 3 white (predominantly European American) grandparents
• serum triglycerides < 400 mg/dl
• fasting glucose < 126 mg/dl

Exclusion Criteria:

• Use of lipid-lowering medication
• Use of over-the-counter products containing sterol or stanol esters or fish oil
• Recent or planned change in dietary intake or weight change of more than 4.5 kg
• Use of corticosteroids, immunosuppressive drugs or drugs affecting the CYP3A4 system
• Known liver disease or elevated transaminase levels
• Elevated creatine phosphokinase levels > 10 times upper limits of normal
• Uncontrolled blood pressure, or diabetes mellitus
• Abnormal renal or thyroid function
• Current alcohol or drug abuse
• Major illness in the preceding three months
• Pregnancy
• Know intolerance to statins
• Racial ancestry other than African-American or Caucasian

The trial was conducted between March 2002 and October 2004.

• Primary Phenotype: Hypercholesterolemia
• Cardiovascular Diseases
• Hydroxymethylglutaryl-CoA Reductase Inhibitors

• Principal Investigator
  • Ronald M. Krauss, MD. University of California San Francisco, Oakland, CA, USA.
• Co-investigator
  • Stephen B. Hulley, MD, MPH. University of California, San Francisco, CA, USA.
  • Joel Simon, MD, MPH. University of California, San Francisco, CA, USA.
  • David Waters, MD. University of California, San Francisco, CA, USA.
  • Mohammed Saad, MD. University of California, San Francisco, CA, USA.
  • Huiying Yang, MD, PhD. Cedars-Sinai Medical Center, Los Angeles, CA. USA.
  • Jerome I. Rotter, MD. Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Deborah Nickerson, PhD. University of Washington, Seattle, WA, USA.
  • Feng Lin, MS. University of Washington, Seattle, WA, USA.
  • Stephen Shiboski, PhD. University of California, San Francisco, CA, USA.
  • Patricia J. Blanche, MS. Children's Hospital Oakland Research Institute, Oakland, CA, USA.
  • Mathew J. Barber, PhD. University of Chicago, Chicago, IL, USA.
  • Lara M. Mangravite. Children's Hospital Oakland Research Institute, Oakland, CA, USA.
  • Craig L. Hyde, PhD. Pfizer Global Research and Development, Groton, CT, USA.
  • Daniel I. Chasman, PhD. Brigham and Women's Hospital, Boston, MA, USA.
  • Joshua D. Smith. University of Washington, Seattle, WA, USA.
  • Catherine A. McCarty, PhD, MPH. Marshfield Clinic Research Foundation, Marshfield, WI, USA.
  • Xiaohui Li, MD, MS. Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Russell A. Wilke, MD, PhD. Vanderbilt University, Nashville, TN, USA.
  • Mark Rieder, PhD. University of Washington, Seattle, WA, USA.
  • Paul T. Williams, PhD. Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Paul M. Ridker. MD. Brigham and Women's Hospital, Boston, MA, USA.
  • Aurobindo Chatterjee PhD. Pfizer Global Research and Development, Groton, CT, USA.
  • Matthew Stephens, PhD. University of Chicago, Chicago, IL, USA.
  • Marisa W. Medina, PhD. University of California San Francisco, Oakland, CA, USA.
  • Elizabeth Theusch, PhD. University of California San Francisco, Oakland, CA, USA.
• Institute
  • National Heart, Lung, Blood Institute, Bethesda, MD, USA.
• Funding Source
  • U01 HL69757. National Institutes of Mental Health, Bethesda, MD, USA.