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The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease.

ABSTRACT: we tested the hypothesis that the 9p21 risk locus promotes atherosclerosis by examining the association between rs10757278 and coronary artery disease (CAD) severity and progression determined by semi-quantitative angiographic scores.the rs10757278 single nucleotide polymorphism (SNP) was genotyped as the marker for the 9p21 locus in 2334 Caucasian patients undergoing cardiac catheterization (mean age 63, male 67%). Angiographic CAD was assessed using two semi-quantitative scoring systems with one estimating severity (Gensini) and the other extent (Sullivan). A subset of 308 patients who underwent two or more coronary angiograms at least 6 months apart were examined for net change in Gensini and Sullivan scores over time to determine the rate of CAD progression by genotype and were further classified as 'progressors' or 'non-progressors' based on absolute change per year in angiographic severity score. We replicated the association between the rs10757278 SNP and myocardial infarction and binary (presence/absence) angiographic classifications of CAD. Furthermore, we observed a significant additive association with this SNP, and both severity and extent of CAD using angiographic scores, after adjustment for age, gender, body mass index, traditional cardiovascular risk factors, myocardial infarction, and statin use (Gensini P = 0.016, Sullivan P = 0.005). In addition, there was a significant linear association with CAD progression before and after adjustment for covariates (Gensini P = 0.023, Sullivan P = 0.003) with homozygotes for the risk variant having three-fold greater odds of CAD progression compared with the referent group.the 9p21 risk locus is associated with angiographically defined severity, extent, and progression of CAD, suggesting a role for this locus in influencing atherosclerosis and its progression.

SUBMITTER: Patel RS

PROVIDER: S-EPMC3001587 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease.

Patel Riyaz S RS Su Shaoyong S Neeland Ian J IJ Ahuja Ayushi A Veledar Emir E Zhao Jinying J Helgadottir Anna A Holm Hilma H Gulcher Jeffrey R JR Stefansson Kari K Waddy Salina S Vaccarino Viola V Zafari A Maziar AM Quyyumi Arshed A AA

European heart journal 20100820 24

<h4>Aims</h4>we tested the hypothesis that the 9p21 risk locus promotes atherosclerosis by examining the association between rs10757278 and coronary artery disease (CAD) severity and progression determined by semi-quantitative angiographic scores.<h4>Methods and results</h4>the rs10757278 single nucleotide polymorphism (SNP) was genotyped as the marker for the 9p21 locus in 2334 Caucasian patients undergoing cardiac catheterization (mean age 63, male 67%). Angiographic CAD was assessed using two ...[more]

PMID: 20729229

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Project description:BackgroundCase-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.MethodsExtensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.ResultsOnly Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.ConclusionWe conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.

Project description:ObjectiveFibroblast growth factor 23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and is associated with coronary artery calcification, and has been implicated in the pathogenesis of cardiovascular disease. The aim of this study was to determine whether circulating FGF23 concentration is independently associated with the severity and extent of coronary artery disease in patients undergoing coronary angiography.MethodA cross-sectional design was used to examine the relationship between serum FGF23 and the severity and extent of coronary artery stenosis in 2076 patients undergoing coronary angiography (1263 male and 813 female, mean aged 62.5 years). Subgroup analyses were performed to assess the associations between FGF23 and coronary arterial plaque characteristics evaluated by intravascular ultrasound and 12-month incidence of target vessel revascularization (TVR) and target lesion revascularization (TLR).FindingsWe found a stepwise increase of serum FGF23 concentrations in patients with mild, moderate, severe stenosis or with increased number of stenotic vessels compared with those without stenosis (P<0.001). Serum FGF23 concentration was positively correlated with stenosis scores as the global index of the severity and extent of coronary artery stenosis in both male and female (r = 0.315 and r = 0.291, P<0.001). In multiple regression analyses, serum FGF23 concentration was a significant determinant of the stenosis scores independent of other traditional risk factors (standardized β = 0.326, P<0.001). Furthermore, subgroup analyses found FGF23 was significantly associated with plaque and dense calcium volumes. Multiple logistic regression analyses showed that serum FGF23 levels were significantly independent predictors of TVR and TLR.ConclusionsWe report an independent association between circulating FGF23 concentration and the severity and extent of coronary artery stenosis in the coronary angiographic patients. Future studies are needed to elucidate the potential biological mechanisms and whether FGF23 is a modifiable cardiovascular risk factor.

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The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease.

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The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease.

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