Published Online
on April 21, 2009

A more recent version of this article appeared on June 1, 2009

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Original Article

Impact of adding a single allele in the 9p21 locus to traditional risk factors on reclassification of coronary heart disease risk and implications for lipid-modifying therapy in the Atherosclerosis Risk in Communities (ARIC) study

Ariel Brautbar¹; Christie M. Ballantyne^1,7; Kim Lawson²; Vijay Nambi³; Lloyd Chambless⁴; Aaron R. Folsom⁵; James T. Willerson⁶ and Eric Boerwinkle²

¹ Baylor College of Medicine, Houston, TX;
² University of Texas–Houston Health Science Center, Houston, TX;
³ Methodist DeBakey Heart Vascular Center & Baylor College of Medicine, Houston, TX;
⁴ University of North Carolina, Chapel Hill, NC;
⁵ University of Minnesota School of Public Health, Minneapolis, MN;
⁶ Texas Heart Institute & the University of Texas–Houston Health Science Center, Houston, TX

⁷ E-mail: cmb{at}bcm.tmc.edu

Background—A single nucleotide polymorphism on chromosome 9p21, rs10757274 (9p21 allele), has been shown to predict coronary heart disease (CHD) in whites. We evaluated whether adding the 9p21 allele to traditional risk factors (RF) improved CHD risk prediction in whites from the Atherosclerosis Risk in Communities (ARIC) study, and whether changes in risk prediction would modify lipid therapy recommendations.

Methods and Results—Whites (n=9,998) in the ARIC study for whom the 9p21 genotype and traditional RF information was available were included. Using Cox proportional hazards models, the ARIC Cardiovascular Risk Score (ACRS) which is based on traditional RF, was determined. A total of 1,349 individuals (13.5%) developed incident CHD events during a period of 14.6 years. Adding the 9p21 allele to traditional RF was associated with hazard ratio (HR) of incident CHD of 1.2 per allele (p<0.000003) and a significant increase in the area under the curve of the receiver operating characteristic from 0.782 to 0.786 (95% CI= [0.001, 0.007]). The 9p21 allele's greatest influence to the ACRS was observed in the intermediate-low (>5% to 10% 10-year CHD risk) and intermediate-high (>10% to 20% 10-year CHD risk) categories with 12.1% and 12.6% reclassified, respectively. This may impact therapy since 90% of these reclassified individuals had LDL-C>100 mg/dL.

Conclusion—Adding the 9p21 allele to traditional RF in whites in the ARIC study modestly improved CHD risk prediction in the intermediate categories.

Key Words: genetics • heart diseases • lipids • risk factors