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Children's hospital to participate in study of single nucleotide polymorphisms
(Genomics & Genetics Weekly)
2005 NOV 18 - (NewsRx.com) -- Illumina, Inc. (ILMN) announced that it has signed an agreement with Children's Hospital Oakland Research Institute (CHORI) to provide reagents and instrumentation for a study aimed at determining the impact of single nucleotide polymorphisms (SNPs) on individual response to statins.
The study is being carried out as part of the U.S. National Institutes of Health (NIH)-funded research program, "Pharmacogenomics and Risk of Cardiovascular Disease "(PARC). At the end of the current 5-year grant period, PARC aims to have identified critical genetic determinants of response to statin therapy that could be used by health care providers to ensure the best cardiovascular outcome and the lowest risk of treatment for each patient.
The PARC research program is led by Principal Investigator Ronald Krauss, M.D, senior scientist and director of atherosclerosis research, at CHORI. Genotyping will be directed by Coprincipal Investigator Deborah Nickerson, PhD, professor of genome sciences at the University of Washington.
Data analysis will be overseen by Coprincipal Investigator Jerome Rotter, MD, board of governors' chair in medical genetics and director of research, Medical Genetics Institute at Cedars-Sinai Medical Center in Los Angeles, California. Other investigators with key roles in PARC include Mark Rieder, PhD of the University of Washington, Paul Ridker, MD and Dan Chasman, PhD of Brigham and Women's Hospital and Harvard Medical School, Paul Williams, PhD of Lawrence Berkeley National Laboratory, and Russell Wilke, MD of Marshfield Clinic.
As a team, the PARC investigators have expertise in every aspect of the project, including genomics, statistical genetics and informatics, clinical pharmacology and cardiology, laboratory measurements of cardiovascular risk factors, and epidemiology.
The experimental plan divides the study into four sequential phases to ensure adequate statistical power and minimize the risk of false positive results in identifying the most informative SNPs associated with statin response and clinical cardiac endpoints. Statin response phenotypes to be evaluated include levels of LDL and HDL (low- and high-density lipoproteins) and their subfractions, indices of cholesterol synthesis and absorption, and inflammatory markers. The study also aims to identify SNPs associated with statin-related myopathy, an uncommon side effect characterized by damaged muscles.
Sample genotyping for all phases will be performed in Nickerson's laboratory with a new, fully automated Illumina BeadStation system and four leased Illumina BeadArray Readers to accommodate the sample throughput planned in the project schedule. Samples will be drawn from large clinical trials previously carried out by investigators in PARC and other research programs that have tested effects of the statin drugs simvastatin, pravastatin, rosuvastatin and atorvastatin on laboratory and clinical measures of cardiovascular disease risk.
Phase I will involve whole-genome association analysis of over one thousand clinical samples using the Sentrix Human-1 BeadChip and a follow-on Sentrix HumanHap-1 BeadChip that can query over 250,000 TagSNPs (see note) derived from the International HapMap Project.
The study will use Illumina's powerful Infinium assay, which enables the intelligent selection and analysis of virtually any SNP in the genome, providing coverage and multiplex levels that are limited only by the number of features on the BeadChip. Infinium performance, as measured by call rate, accuracy and reproducibility, is comparable to Illumina's GoldenGate assay protocol, the gold standard of the HapMap Project.
Following confirmatory analysis of phase I findings on additional clinical samples and cohorts, subsequent phases will systematically evaluate haplotype blocks, specific haplotypes within each block, and SNPs within those haplotypes to identify the most informative variants and those that have causal association with clinical phenotypes. Over 10,000 samples will be tested in the latter phases of the project, which will employ fine mapping techniques using Illumina's GoldenGate assay protocol, custom panels of SNP markers, and Sentrix Universal Array Matrices.
Children's Hospital & Research Center at Oakland is a designated level I pediatric trauma center and the largest pediatric critical care facility in the region.
Illumina develops and markets next-generation tools for the large-scale analysis of genetic variation and function.
This article was prepared by Genomics & Genetics Weekly editors from staff and other reports. Copyright 2005, Genomics & Genetics Weekly via NewsRx.com.
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