Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility

Anderson, Jeffrey L.; Horne, Benjamin D.; Kolek, Matthew J.; Muhlestein, Joseph B.; Mower, Chrissa P.; Park, Namje; May, Heidi T.; Camp, Nicola J.; Carlquist, John F.

doi:10.1016/j.ahj.2008.07.006

Cited by 63 publications

(54 citation statements)

References 30 publications

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“…These observations were in line with the report by Anderson et al (12), and suggested that variants at the 9p21 locus may robustly predict the prevalence of angiographic CAD, but not angiographic CAD severity. Assimes et al revealed that chromosome 9p21 variation was associated with total coronary plaque burden as expressed by calcification scores (13).…”

Section: Discussionsupporting

confidence: 81%

Chromosome 9p21 polymorphism is associated with myocardial infarction but not with clinical outcome in Han Chinese

Peng¹,

Lü²,

Zhang³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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Background: rs1333049 polymorphism on chromosome 9p21 has been shown to affect susceptibility to coronary artery disease (CAD) in Caucasians. This study examined the association of rs1333049 with myocardial infarction (MI), angiographic severity of CAD and clinical outcome after a first acute MI in Han Chinese. Methods: rs1333049 polymorphism was genotyped in 520 patients with a first acute MI and in 560 controls. The number of angiographically documented diseased coronary arteries (luminal diameter stenosis G50%), echocardiographic left ventricular ejection fraction (LVEF), and major adverse cardiac events (MACE) during follow-up (mean, 29"15 months) were recorded. Results: Patients with MI had higher frequencies of the CC genotype (30.0% vs. 20.7%) or C allele (55.5% vs. 46.2%) compared with controls (all p-0.01). rs1333049 polymorphism was strongly associated with MI wodds ratio (OR) 1.48, 95% confidence interval (CI) 1.22-1.79x after adjusting for traditional risk factors. Although longer hospitalization stay was observed in patients with the rs1333049-C allele, this polymorphism was not related to angiographic severity of CAD, LVEF, and occurrence of MACE after MI. Conclusions: This study demonstrates an association of rs1333049 polymorphism locus on chromosome 9p21 with risk for MI, but not with post-MI prognosis in Han Chinese. Clin Chem Lab Med 2009;47:917-22.

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Section: Discussionsupporting

confidence: 81%

Chromosome 9p21 polymorphism is associated with myocardial infarction but not with clinical outcome in Han Chinese

Peng¹,

Lü²,

Zhang³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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“…This role was assessed in a population of cases with early-onset CAD and confirmed in an independent population with late-onset CAD. The role of 9p21 as a predictor of CAD severity has since been confirmed by multiple investigators (47)(48)(49)(50)(51). The 9p21 risk factor in individuals with early-onset CAD carries a 50% increased risk in heterozygotes and a 2-fold increased risk in homozygotes (19 ), comparable to the 2-fold increased risk of a current smoker (59 ), the 40% increased risk of a 10-mm increase in blood pressure (60 ), and the 30% increased risk associated with a standard deviation increase in LDL cholesterol or a standard deviation decrease in HDL cholesterol (61 ).…”

Section: Should Genetic Risk Variants Be a Part Of A Routine Clinicalmentioning

confidence: 82%

“…Interestingly, there was only a minimal association between 9p21 risk and myocardial infarction. Several other studies have since confirmed the close association of the 9p21 risk allele with atheroma without any association with myocardial infarction (47)(48)(49)(50)(51). Some studies have suggested that 9p21 initiates the process of atherosclerosis rather than being related to its progression or severity (47 ).…”

Section: The Site Of Action For the 9p21 Variant Is The Vessel Wallmentioning

confidence: 99%

9p21 and the Genetic Revolution for Coronary Artery Disease

Roberts

Stewart

2012

Clinical Chemistry

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BACKGROUND It has long been recognized that 50% of the susceptibility for coronary artery disease (CAD) is due to predisposing genetic factors. Comprehensive prevention is likely to require knowledge of these genetic factors. CONTENT Using a genomewide association study (GWAS), the Ottawa Heart Genomic Study and the deCODE group simultaneously identified the first genetic risk variant, at chromosome 9p21. The 9p21 variant became the first risk factor to be identified since 1964. 9p21 occurs in 75% of the population except for African Americans and is associated with a 25% increased risk for CAD with 1 copy and a 50% increased risk with 2 copies. Perhaps the most remarkable finding is that 9p21 is independent of all known risk factors, indicating there are factors contributing to the pathogenesis of CAD that are yet unknown. 9p21 in individuals with premature CAD is associated with a 2-fold increase in risk, similar to that of smoking and cholesterol. Routine genetic testing will probably remain controversial until a specific treatment is developed. Over a period of 5 years, however, GWASs have identified 30 genetic variants for CAD risk, of which only 6 act through the known risk factors. SUMMARY The 9p21 variant has now been established as an independent risk factor for CAD and, along with the additional 29 risk genetic variants recently identified, is likely to provide the thrust for genetic testing and personalized medicine in the near future.

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“…These SNPs seem to influence vascular cell proliferation [8] and some studies have suggested that there are associations between the SNPs on chromosome 9p21 and coronary [9,10], carotid [11] and peripheral [12] atherosclerosis. However, other studies have shown either no or uncertain associations between these SNPs and the extent of coronary atherosclerosis [13,14] or early markers of carotid atherosclerosis [15][16][17][18][19]. Thus, whether or not there is an association between SNPs on chromosome 9p21 and generally increased atherosclerosis remains unclear.…”

Section: Introductionmentioning

confidence: 93%

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

Hamrefors

Hedblad

Engström

et al. 2011

Journal of Internal Medicine

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Abstract. Hamrefors V, Hedblad B, Engström G, Almgren P, Sjögren M, Melander O (Lund University, Malmö, Sweden). A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis. J Intern Med 2012;271: 271-281.Objective. To assess whether or not a genetic risk score that was previously shown to be associated with myocardial infarction (MI) and coronary artery disease (CAD) is also associated with markers of carotid atherosclerosis.Design. A total of 4022 middle-aged subjects from the general Swedish population were genotyped and individually assigned a genetic risk score based on 13 single-nucleotide polymorphisms (SNPs), previously associated with MI and CAD. The genetic score (Score-MI) was then related to carotid bulb intimamedia thickness (IMT), common carotid artery (CCA) IMT and to the occurrence of carotid plaques in the study population.Results. Score-MI was associated with IMT of the bulb (P < 0.001) and the CCA (P < 0.001) in unadjusted analyses, and with IMT of the bulb after adjustment for cardiovascular risk factors (P = 0.003). The effect size of Score-MI on IMT of the bulb was similar to that of LDL cholesterol. After adjustment for cardiovascular risk factors, Score-MI was also associated with the occurrence of carotid plaques (odds ratio per quintile of Score-MI = 1.11; 95% confidence interval 1.04-1.18; P = 0.001). In addition to SNPs with known effects on LDL levels, Score-MI showed nominal associations with increasing systolic blood pressure and decreasing C-reactive protein levels.Conclusions. This genetic risk score was independently associated with carotid bulb IMT and carotid plaques, providing evidence of an association with early markers of atherosclerosis. This might imply that the genetic MI risk conferred by the score is related to early atherosclerosis and that the risk score may identify at an early stage candidates at risk of developing intermediate phenotypes of atherosclerosis. Further studies should test whether or not assessing the genetic score could be valuable for early treatment decisions in these subjects.

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Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility

Cited by 63 publications

References 30 publications

Chromosome 9p21 polymorphism is associated with myocardial infarction but not with clinical outcome in Han Chinese

Chromosome 9p21 polymorphism is associated with myocardial infarction but not with clinical outcome in Han Chinese

9p21 and the Genetic Revolution for Coronary Artery Disease

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

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