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Detection of a group of risk factors in coronary disease using a new carriership analysis approach

      The oligogenic basis for phenotypic traits in common diseases is difficult to identify since any 1 genotype may have only a small effect on the disease process, thus obscuring its contribution to the trait.
      • Tanksley S.D.
      Mapping polygenes.
      ,
      • Lander E.S.
      • Schork N.J.
      Genetic dissection of complex traits.
      Schork et al
      • Schork N.J.
      • Kreiger J.E.
      • Trolliet M.R.
      • Franchini K.G.
      • Koike G.
      • Krieger E.M.
      • Lander E.S.
      • Dzau V.J.
      • Jacob H.J.
      A biometrical genome search in rats reveals the multigenic basis of blood pressure variation.
      investigated the multigenic basis of blood pressure variation in selectively bred rats and found an additive effect of several deleterious genotypes on blood pressure. We have extended this approach to clinical coronary artery disease (CAD) and hypothesized that each of several relevant phenotypic or genotypic risk factors makes a small yet additive contribution to time-dependent outcome events. Our analytic approach assigns to each subject in a study population a score based on the number of prespecified risk factors carried by the subject, and this risk score is related to outcome events using a standard time-dependent survivorship analysis.
      • Cox D.R.
      Regression models and life-tables.
      The computed hazard ratio for the population is expressed as the average increase in risk for each risk factor present. A hazard ratio significantly >1.0 indicates that the prespecified risk factors jointly increase the risk for outcome events. This approach can identify an average risk effect without implicating a specific factor, permits covariate adjustment for relevant environmental factors, and incorporates exposure time in the analysis. Because an at-risk subject may “carry” several risk factors, we have applied the term “carriership analysis” to succinctly describe our analytic approach. We have applied this carriership approach to a recently reported clinical study of patients with coronary disease

      Moss AJ, Goldstein RE, Marder VJ, Sparks CE, Oakes D, Greenberg H, Weiss HJ, Zareba W, Brown MW, Liang C, Lichstein E, Little WC, Gillespie JA, Van Voorhees L, Krone RJ, Bodenheimer MM, Hochman J, Dwyer EM Jr, Arora R, Marcus FI, Miller Watelet LF, Case RB. Thrombogenic factors and recurrent coronary events. Circulation 1999;99:25176–2522.

      using phenotypic hemostatic, lipid, and metabolic risk factors. We then conducted simulated genetic analyses for a hypothetical set of risk genotypes with various allelic frequencies and different risk effects.
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