Abstract 15997: Adding Genetic Markers to Classic Risk Factors - An Enhanced Coronary Risk Score Based on the Morgam Prospective Cohorts
Introduction: Genome wide association studies have uncovered single nucleotide polymorphisms associated with CHD. These discoveries may improve the prediction of incident CHD if added to classic risk scores. Improvement would be clinically most relevant for those with intermediate risk (10-20%) by classic cardiovascular risk scores.
Hypothesis: We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and that more precise risk estimates could be obtained using a prospective cohort design.
Methods: Using data from nine prospective European cohort studies, including 39,168 individuals, we selected, in a case-cohort setting, 6,352 men and women who were healthy at baseline and used Cox proportional hazards models to examine the associations between CHD and risk variants from 13 genomic regions. Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 included the 11 SNPs plus the 4 SNPs from the haplotypes with coefficients estimated directly from these prospective cohorts using 10-fold cross-validation. Scores were added to a baseline model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.
Results: Over follow-up (range: 5 - 18 years), 1,998 incident CHD events occurred. Genetic risk scores were validated using cohorts with at least 10 years' follow-up comprising 632 cases and 1361 non-cases. Both scores improved net reclassification over the Framingham score (7.5%, p=0.017 for GRS1, 6.5%, p=0.044 for GRS2) but GRS2 also improved discrimination (c-index increasing by 1.11%, p=0.048). Reclassification improvement was most striking for those at intermediate risk based on the classic risk factors (431 cases, 664 non cases) with a clinical net reclassification improvement of 17.0% (p=0.0004) for GRS1 and 17.9% (p=0.0004) for GRS2. Even when family history of CHD was added to the baseline model for a subgroup of men aged 50-59 (434 cases and 593 non-cases), both scores improved CHD prediction.
Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle-aged men at intermediate risk.
- © 2011 by American Heart Association, Inc.