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

doi:10.1016/j.ahj.2008.07.006

American Heart Journal

Volume 156, Issue 6, December 2008, Pages 1155-1162.e2

https://doi.org/10.1016/j.ahj.2008.07.006 Get rights and content

Background

Variants at the 9p21 locus have been associated with coronary heart disease, but their precise disease phenotype and utility for clinical risk assessment are uncertain.

Methods

Consenting patients with early-onset angiographic coronary artery disease (CAD) (n = 1,011) were compared with matched subjects (n = 545) free of angiographic disease and with a random population sample (n = 565). Cases and controls were genotyped for 4 variants, and ORs for angio-CAD were determined. Findings were validated in a separate set of cases and controls (n = 1,452).

Results

Alleles were highly correlated (r² ≥ 0.9), and all predicted angio-CAD compared with both control groups. Genotype at rs2383206 (minor allele frequency 45.9%), the most predictive (P < .0001), was associated with an adjusted odds ratio for angio-CAD of 1.39 (95% CI, 1.05–1.85) for heterozygote and 1.73 (1.26–2.37) for homozygote risk-allele carriers and explained 21% of population attributable risk and was independent of traditional risk factors and myocardial infarction. For the comparison of combined cases versus combined control samples (N = 3,573), CAD was predicted by high-risk allele homozygosity at P = 9 × 10⁻⁸. Despite this, extent of disease was not increased. Applied to patients with intermediate Framingham risk scores, 9p21 genotyping modified risk classification in 24%.

Conclusions

Variants at the 9p21 locus robustly predict angiographic CAD prevalence, independent of standard risk factors, but not CAD extent or myocardial infarction; provide pathophysiological insights; and may be clinically useful in refining coronary heart disease risk classification.

Section snippets

Objectives

The primary study objectives were (1) to prospectively assess the association of four 9p21 variants in patients with early-onset, angiographically defined CAD compared with (a) matched angiographically healthy subjects and with (b) a random population sample; (2) to validate the initial findings in a separate set of cases and controls; (3) to assess the association of the 9p21 variants with 8 traditional and 2 novel (inflammatory) risk factors and with CAD distinct from myocardial infarction

Patient characteristics

Characteristics of the initial association set of cases and controls are summarized in Table I. As expected, traditional risk factors were more prevalent in cases than either control group. Lipid profile and blood pressure were more favorable in population controls, whereas they were more similar in angiographic controls compared to cases. Levels of hsCRP and LpPLA2 were higher in cases.

SNP distributions and cross correlations

Allelic frequencies and representative genotypes in the initial case and control sample sets are shown in

Summary of key results

This large study, representing a total of 3573 cases and controls, prospectively assessed and validated the value of highly correlated genetic sequence variants at 9p21.3 to predict the specific CHD phenotype of angiographic CAD in a geographically distinct, primarily Caucasian population. The study demonstrated several levels of internal consistency and was statistically robust: a precise phenotype for cases and controls was established angiographically; findings among the 4 highly linked SNPs

Conclusions

In this large, angiographically defined case-control study, variants at the 9p21 locus were found to robustly predict CAD prevalence independent of standard risk factors, extent of disease, and MI. Taken together, these results suggest a specific role for 9p21 in atherosclerosis initiation/promotion. Finally, 9p21 genotyping appears to be useful in refining risk classification in those at intermediate risk and deserves prospective clinical testing as a novel risk marker.

References (33)

WilliamsR.R. et al.
Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study)
Am J Cardiol
(2001)
HorneB.D. et al.
Multiple-polymorphism associations of seven matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease
Am Heart J
(2007)
RosamondW. et al.
Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and the Stroke Statistics Subcommittee
Circulation
(2007)
YusufS. et al.
Global burden of cardiovascular diseases, part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization
Circulation
(2001)
YusufS. et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study
Lancet
(2004)
MarenbergM.E. et al.
Genetic susceptibility to death from coronary heart disease in a study of twins
N Engl J Med
(1994)
ZdravkovicL. et al.
Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins
J Intern Med
(2002)
WienkeA. et al.
The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins
Twin Res
(2001)
HopkinsP.N. et al.
Family history and genetic factors
TopolE.J. et al.
Genetic susceptibility to myocardial infarction and coronary artery disease
Hum Molec Genet
(2006)

AndersonJ.L. et al.

Progress in unraveling the genetics of coronary artery disease and myocardial infarction

Curr Atheroscl Rep

(2007)

IoannidisJ.P.A. et al.

Replication validity of genetic association studies

Nat Genet

(2001)

HegeleR.A.

SNP judgments and freedom of association

Arterioscler Thromb Vasc Biol

(2002)

MorganT.M. et al.

Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study

JAMA

(2007)

YamadaY.H. et al.

Prediction of the risk of myocardial infarction from polymorphisms in candidate genes

N Engl J Med

(2002)

ChanockS.J. et al.

Replicating genotype-phenotype associations

Nature

(2007)

Cited by (62)

Gene-environment interactions that influence CVD, lipid traits, obesity, diabetes, and hypertension appear to be able to influence gene therapy
2023, Molecular Aspects of Medicine
Most mind boggling diseases are accepted to be impacted by both genetic and environmental elements. As of late, there has been a flood in the improvement of different methodologies, concentrate on plans, and measurable and logical techniques to examine gene-environment cooperations (G × Es) in enormous scope studies including human populaces. The many-sided exchange between genetic elements and environmental openings has long charmed the consideration of clinicians and researchers looking to grasp the complicated starting points of diseases. While single variables can add to disease, the blend of genetic variations and environmental openings frequently decides disease risk. The fundamental point of this paper is to talk about the Gene-Environment Associations That Impact CVD, Lipid Characteristics, Obesity, Diabetes, and Hypertension Have all the earmarks of being Ready to Impact Gene Therapy. This survey paper investigates the meaning of gene-environment collaborations (G × E) in disease advancement. The intricacy of genetic and environmental communications in disease causation is explained, underlining the multifactorial idea of many circumstances. The job of gene-environment cooperations in cardiovascular disease, lipid digestion, diabetes, obesity, and hypertension is investigated. This audit fixates on Gene by Environment (G × E) collaborations, investigating their importance in disease etiology.
The association between a variant of the cyclin-dependent kinase inhibitor 2A/B gene and risk of cardiovascular disease
2022, Gene Reports
Citation Excerpt :
The GWAS studies on CVDs are still relatively limited. Among the loci, which have been proposed to be involved in the predisposition to CVDs, the 9p21 locus appears to be of importance, according to studies in the UK, Japan, South Korea, Germany and Italy (Hinohara et al., 2008; Anderson et al., 2008). Single nucleotide polymorphisms at the 9p21 locus have also been showed to be associated with sudden cardiac death (SCD), CAD and to myocardial infarction (MI) in a primary and secondary prevention setting (Bressler et al., 2010; Larson et al., 2007; Ivanova et al., 2017).
Cardiovascular disease (CVD) is the most common cause of morbidity and mortality globally. Despite progress being made in the diagnosis and treatment of CVDs, one third of deaths are due to CVDs. We have investigated the association between the rs1333049 polymorphism of the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene with CVD outcomes in a population sample recruited as part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort.
Five hundred and nine individuals who had a median follow-up period of 10 years were recruited as part of the MASHAD cohort. Anthropometric, and biochemical parameters were assessed followed by genotyping using TaqMan-real-time-PCR based method. Our data showed that carriers of the GG genotype were significantly more likely to develop CVD, compared to those with a CC or CG genotypes (OR: 4.77, 95%CI: 2.62–8.68, p = 0.001). Similar result we also found in second population which were follow up for 10 years. In particular cases who had an event in recessive genetic model (CC vs CG + GG) had a higher risk of developing CVD (OR: 5.57, 95%CI: 2.80–11.06, p = 0.001).
We have found that carriers of the GG genotype of the CDKN2A/B gene locus were at increased risk of CVD in a representative population-based cohort, indicating further functional analysis to explore the value of emerging marker as a risk stratification biomarker to identify high risk cases.
The Association of ANRIL With Coronary Artery Disease And Aortic Aneurysms, How Far Does The Gene Desert Go?
2022, Annals of Vascular Surgery
Citation Excerpt :
Since the discovery of the role of the gene locus on chromosome 9p21 in CAD in 2007, many studies have sought to uncover the SNPs that are most associated with CAD,3,9,22–26 and many have attempted to determine the mechanistic role ANRIL SNPs play in the disease process.4,8,11,27,28 In one of the earliest reports, Anderson et al. in 2008 studied a large cohort of 2,121 Caucasian patients and found that 4 ANRIL SNPs rs2383206, rs2383207, rs10757278 and rs10757274 predicted CAD, when compared with age and sex matched controls (non-angiographic controls, P = 0.012-0.0008; population controls, P = 0.001-<0.0001).24 In particular, they found that rs2383206 with a minor allele frequency of 45.9% was the most predictive SNP (P < 0.0001), and was associated with angiographic CAD for heterozygote (adjusted OR=1.39, 95%CI:1.05-1.85) and homozygote (adjusted OR=1.73, 95%CI:1.26-2.37) risk alleles.
Coronary artery disease (CAD) and aortic aneurysms (AA) are 2 cardiovascular diseases that share a multifactorial aetiology. The influence of family history and genetics on the 2 diseases separately and in association is well known, but poorly elucidated. This comprehensive review aims to examine the current literature on the gene ANRIL (antisense non-coding RNA in the INK4 locus) and its associations with CAD and AA.
A database search on OVID, PubMed and Cochrane to identify articles concerning single nucleotide polymorphisms (SNPs) associated with ANRIL and their respective incidences of, and impact on, CAD and AA across populations.
Cohort studies across various ethnicities reveal that various ANRIL SNPs are significantly associated separately with CAD (rs1333040, rs1333049 and rs2383207) and AA (rs564398, rs10757278 and rs1333049), and that these SNPs are present in significant proportions of the population. SNP rs1333049 is significantly associated with both diseases, but is positively correlated with AAA and negatively correlated with CAD. This review further outlines several pathophysiological links via endothelial and adventitial cells, vascular smooth muscle cells and sense gene interaction, which may explain these genetic associations identified.
Given the associations uncovered between ANRIL polymorphisms and CAD and AA, as well as the molecular mechanisms which may explain the underlying pathophysiology, ANRIL appears to be strongly linked with both diseases. ANRIL may hence have a future application in screening normal patients and risk stratifying patients with both diseases. Its role in linking the 2 diseases is yet unclear, warranting further studies.
The 9p21.3 locus and cardiovascular risk in familial hypercholesterolemia
2017, Journal of Clinical Lipidology
Carrying a risk variant in the 9p21.3 locus represents one of the strongest genetic risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, the effect of these polymorphisms in patients with familial hypercholesterolemia (FH) has never been studied.
The objective of this study was to investigate the association between the sentinel 9p21.3 single nucleotide polymorphisms (SNP) rs1333047 and ASCVD susceptibility in FH subjects.
A total of 20,434 Caucasian patients with dyslipidemia were screened, of which 725 FH were included in this study. The risk allele (T) of the rs1333047 SNP has previously been shown to confer increased ASCVD risk compared with the control allele (A).
In a model adjusted for traditional cardiovascular risk factors, carrying the risk allele was associated with a 42% increased ASCVD susceptibility per allele, according to an additive model (odds ratio = 1.42; 95% confidence interval, 1.05-1.91; P = .02). On average, 0.53 cardiovascular event was observed in AA carriers, compared with 0.83 in the TT group (P = .02). The mean age of first ASCVD event was similar among the 3 variants.
The 9p21.3 SNP rs1333047 SNP was associated with increased ASCVD in FH subjects. Genetic screening for this SNP could allow to identify very high risk FH patients, which could benefit from more aggressive ASCVD prevention.
Genetic score based on high-risk genetic polymorphisms and early onset of ischemic heart disease in an Italian cohort of ischemic patients
2014, Thrombosis Research
Several single-nucleotide polymorphisms (SNPs) have been recognized as associated with ischemic heart disease (IHD) although the optimal set of risk genotypes has not be identified. This study aimed to examine whether identified high-risk SNPs are associated with early onset of IHD. In the GENOCOR study, 44 high-risk SNPs were genotyped in 114 patients with early onset of IHD (46.2 ± 5.1 years) and 384 patients with late onset of IHD (60.7 ± 5.9 years). The associations between individual SNPs and early onset IHD were assessed. A multilocus genetic risk score (GRS) for each associated risk genetic markers was constructed by summing the number of risk alleles. The SNPs significantly associated with IHD were: -482C > T of Apolipoprotein C III gene (ApoC3, p = 0.02); 1171 5A > 6A of Matrix metalloproteinase 3 stromelisine I gene (p = 0.01); G98T of Selectin E gene (p = 0.05); C/G of 9p21.3 locus (p = 0.01). Likelihood ratio test showed a strong interaction for increasing risk of early IHD between the presence of ApoC3 and 9p21.3 locus with hypertriglyceridemia (p = 0.0008, 0.0011) as well as between 9p21.3 locus and smoking (p = 0.0010) after correction for multiple testing. The OR for premature IHD for GRS unit was 1.3 (95% CI 1.1-1.6, p = 0.001). Patients in the top tertile of GRS were estimated to have a 3.2-fold (95% CI 1.5-6.8; p = 0.001) increased risk of early IHD compared with those in the bottom tertile. The results show that currently identified high-risk SNPs confer an additive biomarker for cardiovascular events. GRS may provide important incremental information on the genetic component of IHD.
Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: A collaborative meta-analysis
2013, Journal of the American College of Cardiology
Citation Excerpt :
Three large studies have demonstrated further association between 9p21 and CAD burden with a number of diseased vessels or semi-quantitative methods such as the Gensini score, suggesting that 9p21 promotes progressive atherosclerosis (12,13,24). However, other studies have not confirmed this association, and this lack of consistency has led to difficulties in reconciling association with presence but not extent of CAD (14,15). However, this meta-analysis, which includes almost all published and unpublished reports on 9p21 and angiographic CAD, convincingly demonstrates that 9p21 is associated with greater CAD burden, overall.
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

View all citing articles on Scopus

: The study was funded by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (R01HL071878) (both in Bethesda, MD), and the Deseret Foundation, Intermountain Healthcare, Salt Lake City, UT.

: This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

View full text

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

Background

Methods

Results

Conclusions

Section snippets

Objectives

Patient characteristics

SNP distributions and cross correlations

Summary of key results

Conclusions

Am J Cardiol

Am Heart J

Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and the Stroke Statistics Subcommittee

Circulation

Global burden of cardiovascular diseases, part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization

Circulation

Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study

Lancet

Genetic susceptibility to death from coronary heart disease in a study of twins

N Engl J Med

Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins

J Intern Med

The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins

Twin Res

Family history and genetic factors

Genetic susceptibility to myocardial infarction and coronary artery disease

Hum Molec Genet

Progress in unraveling the genetics of coronary artery disease and myocardial infarction

Curr Atheroscl Rep

Replication validity of genetic association studies

Nat Genet

SNP judgments and freedom of association

Arterioscler Thromb Vasc Biol

Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study

JAMA

Prediction of the risk of myocardial infarction from polymorphisms in candidate genes

N Engl J Med

Replicating genotype-phenotype associations

Nature

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