Chromosome 9p21 Single Nucleotide Polymorphisms Are Not Associated With Recurrent Myocardial Infarction in Patients With Established Coronary Artery Disease

Center of Excellence, Health Services Research and Development, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA.
Circulation Journal (Impact Factor: 3.94). 02/2012; 76(4):950-6. DOI: 10.1253/circj.CJ-11-1166
Source: PubMed


Chromosome 9p21 single nucleotide polymorphisms (SNPs) have been shown to be associated with coronary heart disease in multiple studies. The aim of the present study was to identify whether these SNPs are associated with recurrent myocardial infarction (MI), revascularization, or death in acute coronary syndrome (ACS) patients or in those undergoing coronary artery bypass grafting (CABG).
TexGen registry participants with ACS (n=2,067) or CABG (n=1,176) were evaluated, to assess whether 9p21 SNPs (rs1333049, rs2383206, rs10757278, rs10757274) were associated with recurrent MI (primary outcome), recurrent revascularization, or death (secondary outcomes) at approximately 3.2 years of follow-up. Carriers of risk allele (C) for rs1333049 presented at an earlier age (62 vs. 63.5 years in non-carriers, P=0.0004) with more extensive disease (number of vessels with significant stenosis: 1.9 vs. 1.7 in non-carriers, P=0.001) in the ACS group. In adjusted models, the C allele was not associated with recurrent MI (hazard ratio [HR], 1.01; 95% confidence interval [CI]: 0.74-1.38), recurrent revascularization (HR, 0.98; 95%CI: 0.78-1.23), or death (HR, 0.91; 95%CI: 0.69-1.18) in the ACS or CABG groups (recurrent MI: HR, 0.64; 95%CI: 0.40-1.05; recurrent revascularization: HR, 0.98; 95%CI: 0.61-1.55; death: HR, 0.89; 95%CI: 0.61-1.30). Results were similar for the other 3 SNPs.
9p21 SNPs were not associated with recurrent MI, revascularization, or mortality after ACS or CABG. Individuals with the rs1333049 C allele, however, may present with earlier and more extensive disease.

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    • "The literature search retrieved 327 papers, of which 25 (1,5–11,13,17,18,23–36) satisfied our inclusion criteria, reporting data from 33 cohorts (Online Fig. S1). To this we added data that was unpublished at the time from 2 cohorts (Emory [Patel et al., June 2013]; SMART, Second Manifestations of ARTerial disease [Tragante et al., June 2013]). "
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    ABSTRACT: Objectives 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 hazards ratio (HR) of a first event of 1.19 (95% CI: 1.17, 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 (0.97, 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (P-value for heterogeneity= 5.6x10-11). 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.
    Journal of the American College of Cardiology 06/2014; 63(21). DOI:10.1016/j.jacc.2014.01.065 · 16.50 Impact Factor
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    • "In the Global Registry of Acute Coronary Events (GRACE) genetic study, the 9p21 variant showed a significant association with cardiovascular death [16]. However, Virani et al. [17] recently reported that the 9p21 variant was not associated with cardiovascular outcome. In order to clarify the longterm impact of 9p21 variant on cardiovascular mortality in CAD patients, we therefore examined the polymorphism of rs4977574 in a Taiwanese cohort of Han Chinese descent in an eleven-year follow-up duration. "
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    ABSTRACT: Introduction: We examined whether the variant at chromosome 9p21, rs4977574, was associated with long-term cardiovascular mortality in Han Chinese patients with coronary artery disease (CAD). Methodology: Subjects who underwent coronary angiography for chest pain were consecutively enrolled. Fasting blood samples were collected for laboratory and genotype assessments. The information was correlated with data collected from the national death database. Results: There were 925 cases with CAD and 634 without CAD enrolled in the present study. The G allele conferred a significant increase in risk of CAD (odds ratio = 1.47, P = 0.003 in the dominant model; odds ratio = 1.36, P = 0.018 in the recessive model). During a median of 11 years (inter-quartile range between 5.2 and 12.5 years) of follow-up, neither the total nor the cardiovascular mortality was different among CAD subjects with different genotypes. Using Cox regression analysis, genotypes of rs4977574 still failed to predict cardiovascular mortality (hazard ratio = 1.25, P = 0.138 in the dominant model; hazard ratio = 1.05, P = 0.729 in the recessive model). Conclusions: The rs4977574 at chromosome 9p21 is associated with presence of CAD in Han Chinese. However, rs4977574 could not predict cardiovascular mortality in these CAD subjects during the eleven-year period of the study.
    04/2014; 2014:626907. DOI:10.1155/2014/626907
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    • "In 1998, a large shared-care diabetes project was initiated: the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) [10]. Of all the patients that were invited, 90% participated in this study and 10% were excluded or refused to participate. "
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    ABSTRACT: The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined. We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality. Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses. After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18). In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.
    Cardiovascular Diabetology 11/2012; 11(1):138. DOI:10.1186/1475-2840-11-138 · 4.02 Impact Factor
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