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

Ariel Brautbar, Lisa A. Pompeii, Abbas Dehghan, Julius S. Ngwa, Vijay Nambi, Salim S. Virani, Fernando Rivadeneira, André G. Uitterlinden, Albert Hofman, Jacqueline C M Witteman, Michael J. Pencina, Aaron R. Folsom, L. Adrienne Cupples, Christie M. Ballantyne, Eric Boerwinkle

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)421-426
Number of pages6
JournalAtherosclerosis
Volume223
Issue number2
DOIs
StatePublished - Aug 2012

Bibliographical note

Funding Information:
The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts ( HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694 ; National Human Genome Research Institute contract U01HG004402 ; and NIH contract HHSN268200625226C . Infrastructure was partly supported by grant UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Genotyping was funded by the Netherlands Organisation of Scientific Research NWO Investments (175.010.2005.011, 911-03–012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. Abbas Dehghan is supported by NWO grant (Vici, 918-76–619). Dr Brautbar is supported by NIH grant 1P30HL101255-01. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the NIH and Boston University School of Medicine is supported by NIH contract N01–HC–25195.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

Keywords

  • Coronary disease
  • Genetics
  • Risk factors

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