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Genomic prediction of coronary heart disease
Aki S Havulinna,
Oneil G Bhalala,
Sean G. Byars,
Alysha M. De Livera,
Eric J Sijbrands,
Nilesh J Samani,
Posted 26 Feb 2016
bioRxiv DOI: 10.1101/041483 (published DOI: 10.1093/eurheartj/ehw450)
Posted 26 Feb 2016
Background Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of a genomic risk score (GRS) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. Methods We generated a GRS of 49,310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested this using five prospective population cohorts (three FINRISK cohorts, combined n=12,676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n=3,406, 587 incident CHD events). Results The GRS was strongly associated with time to CHD event (FINRISK HR=1.74, 95% CI 1.61-1.86 per S.D. of GRS; Framingham HR=1.28, 95% CI 1.18-1.38), and was largely unchanged by adjustment for clinical risk scores or individual risk factors, including family history. Integration of the GRS with clinical risk scores (FRS and ACC/AHA13 score) improved prediction of CHD events within 10 years (meta-analysis C-index: +1.5-1.6%, P<0.001), particularly for individuals ≥60 years old (meta-analysis C-index: +4.6-5.1%, P<0.001). Men in the top 20% of the GRS had 3-fold higher risk of CHD by age 75 in FINRISK and 2-fold in FHS, and attaining 10% cumulative CHD risk 18y earlier in FINRISK and 12y earlier in FHS than those in the bottom 20%. Furthermore, high genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking. Conclusions A GRS based on a large number of SNPs substantially improves CHD risk prediction and encodes decades of variation in CHD risk not captured by traditional clinical risk scores.
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