Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 63, Issue 21, Pages 2234-2245Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2014.01.065
Keywords
coronary heart disease; genomics; incident; subsequent; 9p21
Categories
Funding
- National Institute for Health Research (NIHR) Clinical Lectureship
- Netherlands Organization for Health Research and Development (ZonMw) [90700342]
- UCL NIHR Biomedical Research Centre
- National Institutes of Health at Emory University [UL1 RR025008]
- NIHR [RP-PG-0407-10314]
- Medical Research Council (MRC) Prognosis Research Strategy (PROGRESS) Partnership [G0902393/99558]
- U.K. MRC Population Health Scientist Fellowship [G0802432]
- Medical Research Council [G0802432, MR/K006584/1] Funding Source: researchfish
- National Institute for Health Research [RP-PG-0407-10314, CL-2011-11-003] Funding Source: researchfish
- MRC [G0802432] Funding Source: UKRI
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Objectives The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis. Background Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear. Methods We searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events. Results We identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = 5.6 X 10(-11)). We found no evidence for biases to account for these findings. Conclusions Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD. (J Am Coll Cardiol 2014; 63: 2234-45) (C) 2014 by the American College of Cardiology Foundation
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