AtherosclerosisThe Path From Genomics to Therapeutics
David T. Miller, MD, PhD*, ,
Paul M. Ridker, MD, MPH, FACC , ,,
Peter Libby, MD, FACC,,* and
David J. Kwiatkowski, MD, PhD*,
* Division of Hematology
Division of Preventive Medicine and Center for Cardiovascular Disease Prevention
Division of Cardiovascular Medicine, Brigham and Women's Hospital
Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Brigham and Women's Hospital and the Harvard Medical School, Boston, Massachusetts
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Figure 1 Genetic Information: SNPs and Haplotypes
The C-reactive protein (CRP) gene structure, single nucleotide polymorphisms (SNPs), and haplotypes; (A)
CRP consists of 2 exons comprising coding regions (darkest shading) and noncoding regions (medium shading) and has 7 common SNPs indicated by rs numbers and relative position. (B) Sequencing traces of a G/C SNP in exon 2 shows the G/G version (black peak, top) and G/C version (black/blue peak, bottom). (C) Different combinations of alleles at each of the 7 SNP positions create 6 common haplotypes for this set of CRP SNPs. Illustration by Rob Flewell.
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Figure 2 Levels of Genomic and Proteomic Information
Capturing all genomic and proteomic information requires a combined approach that targets DNA, RNA, and proteins. The single nucleotide polymorphisms (SNPs) may influence gene expression (e.g., by altering a transcriptional activator binding site in the promoter), or gene function (e.g., by causing an amino acid change). Transcriptional activators (TA), repressors (TR), and mRNA turnover influence mRNA levels independent of SNP genotypes; these mechanisms would only be detectable by expression profiling. Although mRNA levels may vary within and among cells, regulation of protein trafficking, turnover, or structure could affect a protein level or function independently from genotype or mRNA regulation. Illustration by Rob Flewell.
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Figure 3 Coordination of Information for Clinical Decision-Making
Informed clinical decision-making based on genomic information will require synthesis of diverse pieces of data. The relative significance of genomic, proteomic, and metabolomic markers could vary among patients. Such information must be considered in the context of personal medical history, family history, other clinical and laboratory data, and environmental variables. ECG = electrocardiography. Illustration by Rob Flewell.
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