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A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies.

TitleA genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies.
Publication TypeJournal Article
Year of Publication2012
AuthorsBrautbar A, Pompeii LA, Dehghan A, Ngwa JS, Nambi V, Virani SS, Rivadeneira F, Uitterlinden AG, Hofman A, Witteman JCM, Pencina MJ, Folsom AR, L Cupples A, Ballantyne CM
Secondary AuthorsBoerwinkle E
JournalAtherosclerosis
Volume223
Issue2
Pagination421-6
Date Published2012 Aug
ISSN1879-1484
KeywordsArea Under Curve, Coronary Disease, Discriminant Analysis, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Models, Genetic, Multivariate Analysis, Netherlands, Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, ROC Curve, United States
Abstract

OBJECTIVE: Multiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs).

METHODS: SNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS.

RESULTS: The GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07-1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 (Δ = 0.007; 95% CI, 0.004-0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10-1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02-1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest.

CONCLUSION: Addition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies.

DOI10.1016/j.atherosclerosis.2012.05.035
Alternate JournalAtherosclerosis
PubMed ID22789513
PubMed Central IDPMC3595115
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
P30 HL101255 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
/ / Intramural NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
UL1 RR024148 / RR / NCRR NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States