Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: a systematic review and meta-analysis

Abstract

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 × 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.

Keywords: 9p21; coronary heart disease; genomics; incident; subsequent.

Figure 1

Association of Ch9p21 (Per Risk Allele) With First and Subsequent CHD Events During Prospective Follow-Up Forest plot demonstrating study-specific and pooled hazard ratios between Ch9p21 and risk of incident coronary heart disease (CHD) events in general populations (first events) and CHD populations (subsequent events). Covariate adjustments for each study are also provided. TexGen reported data separately for individuals with previous acute coronary syndrome (ACS) (TexGen [ACS]) or coronary artery disease (TexGen [coronary artery bypass graft (CABG)]). Intermountain reported 2 different datasets (a test set [Intermountain 1A] and replication set [Intermountain 1B]). ARIC = Atherosclerosis Risk in Communities Study; CAREMA = The Cardiovascular Registry Maastricht; CCHS = Copenhagen City Heart Study; CHS = Cardiovascular Health Study; CI = confidence interval; EPES = Established Populations for Epidemiological Study; GENECOR = Genetic Mapping for Assessment of Cardiovascular Risk; GRACE = Global Registry of Acute Coronary Events; HR = hazard ratio; IGSEMI = Italian Genetic Study of Early onset MI; INFORM = Investigation of Outcomes From Acute Coronary Syndromes Study; INVEST = International Verapamil SR Trandolapril Study; MALMO DCS = Malmo Diet and Cancer Study; MASS II = Medical, Angioplasty or Surgery Study II; MORGAM = MOnica Risk, Genetics, Archiving, Monograph; NORDIL = Nordic Diltiazem study; REGICOR = Registre Gironí del Cor; SMART = Secondary Manifestation of ARTerial disease; WHI = Women's Health Initiative.

Figure 2

Subgroup Analysis of the Association of Ch9p21 (Per Risk Allele) With First and Subsequent CHD Events Subgroups were chosen a priori. The p value for heterogeneity was obtained from the chi-square test. HWE = Hardy Weinberg Equilibrium; NR = not reported; PCR = polymerase chain reaction; other abbreviations as in Figure 1.

Figure 3

Association of Ch9p21 With Individual and Composite Cardiovascular Outcomes Each outcome is stratified by whether the studies reported adjudication of outcome ascertainment (as reported in Table 1). MI = myocardial infarction; Revasc = revascularization; UA = unstable angina; other abbreviations as in Figure 1.

Figure 4

Funnel Plots of the Association of Ch9p21 (Per Risk Allele) With First and Subsequent CHD Events Both funnel plots appeared symmetrical, supported by formal statistical testing of small study effects using Egger’s test.