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Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges

Reporter: Aviva Lev-Ari, PhD, RN

Methods in Genetics and Clinical Interpretation Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges

Joshua W. Knowles, MD, PhD, Themistocles L. Assimes, MD, PhD, Michaela Kiernan, PhD, Aleksandra Pavlovic, BS, Benjamin A. Goldstein, PhD, Veronica Yank, MD, Michael V. McConnell, MD, Devin Absher, PhD, Carlos Bustamante, PhD, Euan A. Ashley, MD, DPhil and John P.A. Ioannidis, MD, DSc

Author Affiliations

From the Division of Cardiovascular Medicine (J.W.K., T.L.A., A.P., M.V.M., E.A.A.), Stanford Prevention Research Center (M.K., V.Y., J.P.A.I.), Division of General Medical Disciplines (V.Y.), Department of Genetics (C.B.), Department of Health Research and Policy (J.P.A.I.), Stanford University School of Medicine, Stanford, CA; Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA (B.A.G.); HudsonAlpha Institute for Biotechnology, Huntsville, AL (D.A.); Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA (J.P.A.I.).

Correspondence to Joshua W. Knowles, MD, PhD, Stanford University School of Medicine, Division of Cardiovascular Medicine, Falk CVRC, 300 Pasteur Dr, Stanford, CA 94305. E-mail knowlej@stanford.edu

Background

Genome-wide association studies (GWAS) have identified more than 1500 disease-associated single nucleotide polymorphisms (SNPs), including many related to atherosclerotic cardiovascular disease (CVD). Associations have been found for most traditional risk factors (TRFs), including

• lipids,1^,2
• blood pressure/hypertension,3^,4
• weight/body mass index,5^,6
• smoking behavior,7 and
• diabetes.8–13

GWAS have also identified susceptibility variants for coronary heart disease (CHD). The first and, so far, strongest of these signals was found in the 9p21.3 locus, where common variants in this region increase the relative risk of CVD by 15% to 30% per risk allele in most race/ethnic groups.13–20 Subsequent large-scale GWAS meta-analyses and replication studies in largely white/European populations have led to the reliable identification of an additional 26 loci conferring susceptibility to CHD,2^,20–23 all with substantially lower effects sizes compared with the 9p21 locus. Many of these CVD susceptibility loci appear to be conferring risk independent of TRFs and thus cannot currently be assessed by surrogate clinical measures (Table 1). Among the 27 independent loci identified in the most recent large meta-analyses of CVD, 21 were reported not to be associated with any of the TRFs.20^,21

 SOURCE

Circulation: Cardiovascular Genetics 2012; 5: 368-376

doi: 10.1161/ CIRCGENETICS.112.962746