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Title: Assessment of the value of a genetic risk score in improving the estimation of coronary risk

Author
item LLUIS-GANELLA, CARLA - Hospital Del Mar Medical Research Institute
item SUBIRANA, ISAAC - Institute For Medical Research Hospital Del Mar
item LUCAS, GAVIN - Hospital Del Mar Medical Research Institute
item TOMAS, MARTA - Hospital Del Mar Medical Research Institute
item MUNOZ, DANIEL - Hospital Del Mar Medical Research Institute
item SENTI, MARIANO - Hospital Del Mar Medical Research Institute
item SALAS, EDUARDO - Gendiag
item SALA, JOAN - Hospital Josep Trueta
item RAMOS, RAFEL - University Of Girona
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MARRUGAT, JAUME - Hospital Del Mar Medical Research Institute
item ELOSUA, ROBERTO - Hospital Del Mar Medical Research Institute

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/17/2012
Publication Date: 6/1/2012
Citation: Lluis-Ganella, C., Subirana, I., Lucas, G., Tomas, M., Munoz, D., Senti, M., Salas, E., Sala, J., Ramos, R., Ordovas, J.M., Marrugat, J., Elosua, R. 2012. Assessment of the value of a genetic risk score in improving the estimation of coronary risk. Atherosclerosis. 222(2):456-463.

Interpretive Summary: In the last several years many individual genetic factors have been found to associate with risk of coronary heart disease (CHD), but it is not known to what extent the factors conferring increased risk can be added together to form a composite genetic risk score (GRS) to provide better and earlier disease prediction. Thus, the objectives of this study were to first integrate the impact of eight high-CHD risk genetic variants to assess the relationship between this GRS and CHD, and second to investigate whether inclusion of the GRS in the Framingham risk function improved its discriminative capacity. This was undertaken in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537). Our results showed that the GRS improves risk reclassification particularly in the population at intermediate coronary risk. Our data support the potential value of the inclusion of integrated genetic information in classical functions for risk assessment and improved discrimination of future disease risk.

Technical Abstract: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537)(meta-analyzed HR [95%CI]: approximately 1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c-statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group.