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.
1
,
2
Schork et al
3
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.
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
5
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.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.
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References
- Mapping polygenes.Annu Rev Genet. 1993; 27: 205-233
- Genetic dissection of complex traits.Science. 1994; 265: 2037-2048
- A biometrical genome search in rats reveals the multigenic basis of blood pressure variation.Genome Res. 1995; 5: 164-172
- Regression models and life-tables.J R Stat Soc B. 1972; 34: 187-220
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.
- A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis.N Engl J Med. 1996; 334: 1090-1094
- A common prothrombin variant (20210G to A) increases the risk of myocardial infarction in young women.Blood. 1997; 90: 1747-1750
- Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.Blood. 1997; 89: 2817-2821
- Polymorphism in the coagulation factor VII gene and the risk of myocardial infarction.N Engl J Med. 1998; 338: 79-85
- Thrombomodulin gene mutations associated with myocardial infarction.Circulation. 1997; 96: 15-18
- Interaction of coagulation defects and cardiovascular risk factors.Circulation. 1998; 97: 1037-1041
Article info
Publication history
Published online: August 16, 2004
Accepted:
June 2,
2000
Received in revised form:
June 2,
2000
Received:
February 29,
2000
Footnotes
☆This study was supported by research grants HL-48259 and HL-30616 from the National Institutes of Health, Bethesda, Maryland.
Identification
Copyright
© 2000 Excerpta Medica Inc. Published by Elsevier Inc. All rights reserved.
