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The association of 9p21-3 locus with coronary atherosclerosis: a systematic review and meta-analysis.
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PMID:  24906238     Owner:  NLM     Status:  Publisher    
BACKGROUND: Studies suggest that the 9p21-3 locus may influence susceptibility to myocardial infarction. We performed a systematic review and meta-analysis to assess whether this locus is associated with severity of coronary atherosclerosis and adverse clinical outcomes in those with known coronary disease.
METHODS: Multiple electronic databases were searched from inception through August 2012. Studies examining 9p21-3 genotype in patients with known coronary artery disease were included. We extracted the association of the 9p21-3 locus with measures of severity of coronary atherosclerosis [number of diseased vessels, Gensini Score, Duke CAD Prognostic Index (DPI)], angiographic outcomes [change in minimum lumen diameter ([increment]MLD) and number of new lesions at follow-up], and key clinical outcomes (all-cause mortality, recurrent myocardial infarction and the need for coronary revascularization). Relative risks (RR) and weighted mean difference (WMD) were pooled using the random effects models.
RESULTS: 23 cohorts enrolling 16,860 participants were analyzed. There was no significant difference between HR and LR genotypes in terms of all-cause mortality, recurrent myocardial infarction or the frequency of coronary revascularization. HR genotype was associated with increased risk of triple vessel disease (RR = 1.34; 95% CI 1.08-1.65; P = 0.01) and increased baseline Gensini Score (WMD = 5.30; 95% CI 0.66-9.93; P = 0.03). However there was no association with DPI (WMD = 4.00; 95% CI 2.94-10.94; P = 0.26). HR genotype did not predict [increment]MLD or number of new lesions at follow-up.
CONCLUSIONS: Patients of coronary atherosclerosis who carry the high risk genotype of the 9p21-3 allele may be more likely to have multi-vessel CAD. However the effect of this allele on CAD progression and disease specific clinical outcomes are not observed possibly due to diminishing genetic risk following dietary modification and therapy.
Muhammad S Munir; Zhen Wang; Fares Alahdab; Mark W Steffen; Patricia J Erwin; Iftikhar J Kullo; Mohammad Hassan Murad
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Type:  JOURNAL ARTICLE     Date:  2014-6-6
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Title:  BMC medical genetics     Volume:  15     ISSN:  1471-2350     ISO Abbreviation:  BMC Med. Genet.     Publication Date:  2014 Jun 
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Journal ID (nlm-ta): BMC Med Genet
Journal ID (iso-abbrev): BMC Med. Genet
ISSN: 1471-2350
Publisher: BioMed Central
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Copyright © 2014 Munir et al.; licensee BioMed Central Ltd.
Received Day: 10 Month: 2 Year: 2014
Accepted Day: 2 Month: 6 Year: 2014
collection publication date: Year: 2014
Electronic publication date: Day: 6 Month: 6 Year: 2014
Volume: 15First Page: 66 Last Page: 66
PubMed Id: 24906238
ID: 4074865
Publisher Id: 1471-2350-15-66
DOI: 10.1186/1471-2350-15-66

The association of 9p21-3 locus with coronary atherosclerosis: a systematic review and meta-analysis
Muhammad S Munir12 Email:
Zhen Wang3 Email:
Fares Alahdab3 Email:
Mark W Steffen1 Email:
Patricia J Erwin4 Email:
Iftikhar J Kullo5 Email:
Mohammad Hassan Murad1 Email:
1Division of Preventive Medicine, Mayo Clinic, Rochester, MN, USA
2Hospital Medicine, University of Wisconsin Medical Foundation, Madison, WI, USA
3Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN, USA
4Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA
5Division of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA


Coronary artery disease (CAD) remains a worldwide leading cause of mortality. Modification of major environmental risks such as smoking and high cholesterol reduces CAD mortality by 20% to 30% [1]. The presence of a positive family history as a strong risk factor in CAD points to underlying genetic risk factors [2].

Genome wide association studies (GWAS) have identified over 30 risk variants for CAD [3,4]. Of these, the variant on the p arm of chromosome 9 at position 21–3 (9p21-3) is the most well-known and replicated. Many studies have established and replicated the association of the 9p21-3 locus with CAD and myocardial infarction (MI). Other studies have revealed that targeted deletion of the 9p21 non-coding interval leads to excessive proliferation of vascular smooth muscle cells as well as their diminished senescence [5]. Some 9p21 variants also impair the inflammatory response in vascular cell types, which might explain some of the genetic susceptibility underpinning CAD [6]. Variants at this locus have also been associated with a lower ankle-brachial index (ABI), which is a marker of increased risk for death and incident cardiovascular disease (CVD) events [7]. The effect of the 9p21-3 locus on angiographic severity and clinical outcomes in patients with established CAD has been tested by several investigators. However, findings from these reports are conflicting.

We therefore conducted a systematic review and meta-analysis of the published literature investigating the association of the 9p21-3 locus with angiographic CAD severity, progression, and key clinical outcomes.


The reporting of this systematic review complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [8].

Eligible studies were comparative studies of human subjects, provided genotyping was done at the 9p21-3 locus in a population with known coronary artery disease (previous/recent MI, or known epicardial coronary stenosis at enrollment). Applicable study designs included observational studies (case–control, cohort and cross sectional) where an association between the 9p21-3 allele and poor outcome or prognostic marker was reported. Only studies written in English were included due to feasibility.

We searched Ovid MEDLINE from 1948 until August 2012 and Ovid EMBASE, Web of Science and SCOPUS, from inception to August 2012. Subject headings (MeSH, EMTREE) were used: Chromosomes, Pair 9, Coronary artery disease, alleles and atherosclerosis. Keywords (9p21*) were used in Web of Science and Scopus. The detailed search strategy is attached in Additional file 1.

A team of two trained reviewers independently screened all articles identified in the literature search. Discrepancies between the reviewers were resolved through discussions and consensus.

Markers of atherosclerotic severity included number of diseased vessels, Gensini Score and Duke CAD Prognostic Index (DPI). Markers of atherosclerotic severity and coronary disease progression are defined elsewhere [9]. We also assessed change in minimum lumen diameter (∆MLD) and number of new lesions at follow-up. Outcomes of interest included all-cause mortality, recurrent MI, need for coronary revascularization, triple vessel disease, Gensini score, DPI, ∆MLD, and number of new lesions. In studies where all-cause and cause-specific mortalities were separately tested, we analyzed all-cause mortality only.

Recurrent MI was defined any acute coronary syndrome associated with troponin elevation and/or ST segment elevation on electrocardiography (ECG). Need for coronary re-vascularization included surgical and percutaneous procedures performed either at target or non-target coronary vessels.

We extracted details on sample size, mean age, race, the identification (rs number) of the particular SNP genotyped, and outcomes of interest. SNPs previously reported in GWAS studies or in strong linkage disequilibrium with them were considered in the analysis.

In keeping with our goal to determine locus-outcome association we did not limit our analysis to a single SNP but instead tested for all available SNPs published in reports chosen for the meta-analysis. In studies reporting > 1 SNP-outcome association, we chose the SNP not elsewhere tested in other data sets. This allows us to capture all known markers in the locus and test as many markers as possible.

We used the Newcastle-Ottawa Quality Assessment to assess the risk of bias of the included studies [10]. The following items were used: selection of patients, comparability, assessment of exposure and/or outcome, length of follow-up, lost to follow-up. We were unable to assess potential publication bias due to limited number of studies included for each outcome [11].

Genotypes were classified as either homozygous low risk (LR) heterozygous intermediate risk (IR) or homozygous high risk (HR). Study results were variedly reported using recessive [LR vs. (IR + HR)], dominant [(LR + IR) vs. HR)] and additive models [LR vs. IR vs. HR]. For the purpose of this manuscript we included additive models. For dichotomized outcomes, we extracted or calculated relative risk (RR) and its 95% confidence intervals (CI). We then pooled RR across the studies using the DerSimonian and Laird random effects methods with the heterogeneity from the Mantel–Haenszel method [12]. For continuous outcomes, we pooled weighted mean difference (WMD) using the same DerSimonian and Laird random effects methods.

We assessed the optimal information size (OIS), similar to power calculation in clinical trials, to evaluate the minimum sample size required in the literature to reach reliable conclusions [8].

We assessed the consistency of the outcomes by testing heterogeneity using the I2 statistic, where I2 > 50% suggests a high level of heterogeneity [13]. All statistical analyses were conducted using STATA version 12 (StataCorp, College Station, TX).


The literature search yielded 229 studies of which 21 (describing 23 distinct cohorts) met criteria for inclusion. Study selection process is described in (Figure  1). Table  1 lists the studies entered in the meta-analysis together with outcomes tested in each study.

The methodological quality of the included studies was fair, with the majority of them providing adequate representativeness of study patients, comparability between patient groups and sufficiently assessment of exposure and/or outcome (Figure  2). Also, in all of the outcomes, except all-cause mortality, triple vessel disease, and Gensini Score, the total sample size reported in the studies were less than the OIS. We, thus, were unable to reach conclusive findings for these outcomes.

We did not find a significant association between 9p21-3 and all-cause mortality (RR = 1.11; 95% CI 0.88-1.40; p = 0.39, I2 = 51.6%) (Figure  3).

Likewise, no significant association emerged in the meta-analysis of 9p21-3 with recurrent MI in patients with known CAD in the additive model (RR = 1.14; 95% CI 0.92-1.40; p = 0.24; I2 = 7.0%). Table  2 lists the summary statistics for the outcomes.

Four cohorts from 3 studies reported need for re-vascularization. No significant association was identified between 9p21-3 and re-vascularization after development of CAD (RR = 1.11; 95% CI 0.78-1.57; p = 0.56; I2 = 78.1%).

The meta-analysis supported an association between 9p21-3 and triple vessel disease. Homozygotes (HR) for the risk allele had significantly greater risk (RR = 1.34, 95% CI 1.08-1.65, p = 0.01, I2 = 53.8%).

Three studies reported severity of CAD as measured by Gensini score at baseline. Combined analysis of these studies showed 5.30 higher mean Gensini score in the LR group vs. the HR group. This difference was significant (95% CI 0.66-9.93; p = 0.03; I2 = 80.2%). However the DPI which also quantifies CAD severity was not significant in the combined analysis of the two studies reporting it (WMD = 4.00; 95% CI −2.94-10.94; p = 0.26; I2 = 87.5%).

Combined analysis of two studies testing for association of angiographic progression as measured by Δ MLD and number of new lesions at follow-up revealed no association with the 9p21-3 allele. The combined WMD for Δ MLD was 0.07 (95% CI −0.02-0.15; p = 0.15; I2 = 1.0%) and new lesions at follow up was 0.03 (95% CI −0.05-0.10; p = 0.49; I2 = 0.0%).


In this meta-analysis of studies investigating angiographic severity and clinical outcomes in patients with CAD, we found an association of 9p21-3 allele with increased risk of triple vessel disease and greater quantitative severity of atherosclerosis as measured with the Gensini score at baseline. The meta-analysis did not support an association of the allele with angiographic outcomes at follow up or clinical outcomes.

Our findings are consistent with the results of Chan et al. [35] who reported a 23% greater risk of triple vessel disease among high risk homozygotes when compared with their low risk genetic counterparts. Different from Chan’s study, we analyzed more outcomes, including measures of severity of coronary atherosclerosis [number of diseased vessels, Gensini Score, Duke CAD Prognostic Index (DPI)], angiographic outcomes [change in minimum lumen diameter (∆MLD) and number of new lesions at follow-up], and key clinical outcomes (all-cause mortality, recurrent myocardial infarction and the need for coronary revascularization). We have for the first time confirmed an association of the allele with a higher Gensini score in a meta-analysis. In quantitative angiography Gensini score is derived by assigning a severity score to each coronary stenosis according to the degree of luminal narrowing and its geographic importance [28]. The score correlates positively with number of vessel segments involved. Thus it is intuitive that an association of 9p21-3 allele with triple vessel disease would translate into an association with the Gensini score in the same direction. However the lack of association with the DPI was surprising. A positive linear correlation between the Gensini and the DPI score is reported in the literature [9]. It is possible that the analysis of DPI was underpowered due to fewer studies reporting this association compared to those reporting the Gensini score.

We found no association between the 9p21-3 allele and angiographic outcomes. This was also unexpected as the process underlying de-novo atherogenesis would remain unchanged over the course of time. One likely explanation can be index event bias [36]. Conceivably, the risk factors distribution among patients with high genetic risk may have shifted after diagnosis and subsequent lifestyle modification and initiation of therapy.

We found no association between genotypic risk and all-cause mortality among CAD patients. This negative finding is supportive of existing evidence published by Ganna et al. [37] which showed that increased risk of all-cause mortality was associated with polygenic risk factors dispersed across the genome. In a sample of over 16,000 participants, a genome wide risk score derived from 707 published SNPs was associated with a modest 10% increased hazard of death. In our study we tested for association between a single locus in a smaller sample which could have further lowered the likelihood of finding an association.

Most GWAS showing locus-disease association, have shown positive results in conditions which are observed to be heritable. Given that there is no published study reporting heritability of the risk of re-infarction, the genetic risk of recurrent events among survivors of ACS remains less probable; an observation noted in our meta-analysis. Likewise in the case of TLR, which could result either from progression of atherosclerosis or recurrent acute ischemic events, we anticipated no association given the absence of increased risk of disease progression and re-infarction among 9p21-3 carriers.

Our study suffers some important limitations. First, we cannot rule out that our findings may be due to chance as multiple testing had been conducted. However, there is no consensus when this problem should be taken into account and which statistical method should be used in meta-analysis [38,39]. Second, the sample size in most of the outcomes reported in the studies was less than the OIS. Thus, we may not have the power to detect weaker associations. At last, our analyses restricted to association studies as no linkage analyses have identified this allele to be associated with CAD.


Patients of CAD who carry the high risk genotype of the 9p21-3 allele may be more likely to have multi-vessel CAD. However the effect of this allele on CAD progression and disease specific clinical outcomes are not observed possibly due to diminishing genetic risk following dietary modification and therapy.


CAD: Coronary artery disease; GWAS: Genome wide association studies; MI: Myocardial infarction; PRISMA: The preferred reporting items for systematic reviews and meta-analyses statement; DPI: Duke CAD prognostic index; ∆ MLD: Change in minimum lumen diameter; ECG: Electrocardiography; LR: Homozygous low risk; IR: Heterozygous intermediate risk; HR: Homozygous high risk; WMD: Weighted mean difference; RR: Relative risk.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MM and ZW contributed equally to this study. MM carried out study design, study screening, data extraction, and drafted the manuscript. ZW carried out study design, quality appraisal, data analysis, and drafted the manuscript. FA participated in quality appraisal and critically revised the manuscript. MS conducted data extraction, drafted and critically revised the manuscript. PE designed the search strategy and revised the manuscript. IK carried out study design, advised on all methodological issues, drafted and critically revised the manuscript. MHM participated in study design, advised on all methodological issues, drafted and critically revised the manuscript. All authors approved the final version of this manuscript and agreed to be accountable for all aspects of the work

Pre-publication history

The pre-publication history for this paper can be accessed here:

Supplementary Material Additional file 1

Search Strategy.

Click here for additional data file (1471-2350-15-66-S1.docx)

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[Figure ID: F1]
Figure 1 

Flow Chart: PRISMA 2009 Flow Diagram.

[Figure ID: F2]
Figure 2 

Risk of bias of the included studies.

[Figure ID: F3]
Figure 3 

Pooled relative risk of all cause mortality using additive [LR vs. IR vs. HR], dominant [(LR + IR) vs. HR)], and recessive [LR vs. (IR + HR)] models.

[TableWrap ID: T1] Table 1 

Characteristics of the included studies

Study ID Genotyping method SNP: and base position Minor allele frequency Linkage disequilibrium (LD) (reported as D’ or r2) Population (age/(%)male/ethnicity) Baseline diagnosis Outcome/prognostic marker (1) Outcome/prognostic marker (2) Outcome/prognostic marker (3) Comments
Anderson, [14]
with 5′ exonuclease (Taqman) chemistry on the ABI Prism 7000
1759 (59/64%/mixed race with 86% white)
No. diseased vessels
baseline Duke index
Prospective cohort
Chen, [15]
fluorogenic 5′ nucleotidase (Taqman) assays using an ABI PRISM® 7900 HT Real-Time PCR instrument
rs2383206 (chromosomal position: 22,105,026), rs2383207 (chromosomal position: 22,105,959), rs10757278 (chromosomal position: 22,114,477), rs1333049 (chromosomal position: 22,115,503)
rs2383206 = 0.15
D’ rs2383206 – 2383207 = 0.99
212 (48/58%/Chinese)
No. diseased vessels
Case control
D’rs2383206-10757278 = 1.0
D’rs2383206 – rs1333049 = 0.99
Chen, [16]
TaqMan allelic discrimination assays
rs7865618: 22021005
LD of rs7865618, rs1537378, rs1333040 with rs1333049 0.81 ≤ r2 ≤ 0.97
322 (59/84%/white)
no. of new lesions
Case control
Hoppman, [17]
TaqMan allelic discrimination assays
rs7865618: 22021005
LD of rs7865618, rs1537378, rs1333040 with rs1333049 0.81 ≤ r2 ≤ 0.97
2028 (−−/−−%/white)
All-cause mortality
Recurrent MI
Prospective cohort
rs1537378: 22051614
rs1333040: 22073404
rs1333049: 22115503
Peng, [18]
TaqMan single nucleotide polymorphism
rs10757274 and rs1333049 had strong LD (r2 = 0.92)
520 (64/78.7%/Chinese)
All-cause mortality
Recurrent MI
No. diseased vessels
Case control
Newton-Cheh, [19]
Sequenom platform (San Diego, Calif), which resolves allele-specific single-base extension products using mass spectrometry (MALDI-TOF)
rs10757274 backup: rs2383207
Case: 0.54 Control: 0.50
Rs10757274 and rs2383207 are in strong linkage disequilibrium (r2 = 0.87).
466 (−−/--%/whites)
Retrospective case–control study of SCD†. Subgroup analysis compared 124 SCD cases with 342 controls. Both cases and controls had CAD
Ellis, (1) [20] (CDCS)
allelespecific TaqMan genotyping probes
GG: 0.22
860 (67/69.2%/whites)
All-cause mortality
Recurrent MI
Cohort study
Ellis, (2) [20] (PMI)
allelespecific TaqMan genotyping probes
GG: 0.22
607 (62/78.6%/whites)
All-cause mortality
Recurrent MI
Cohort Study
Buysschaert, [21]
iPLEX technology on a MassARRAY
2942 (65/67.9%/whites)
Recurrent MI
Prospective cohort
Compact Analyser (Sequenom Inc., CA, USA). The WTCCC controls: Affymetrix platform (Affymetrix Inc., CA, USA).
Patel, [22]
Centaurus (Nanogen) platform
2334 (63/67%/whites)
No. diseased vessels
baseline Gensini score
Prospective cohort
Muehlschlegel, [23]
Golden Gate assay with an Illumina Bead Station 500G system (Illumina)
846 (−−/--%/whites)
All-cause mortality
Prospective cohort
Dandona, [24]
Affymetrix (Santa Clara, California) 500 K and 6.0 arrays
rs9632884 was linkage disequilibrium with rs1333049 (r2 = 0.832).
1714 (−−/--%/whites)
No. diseased vessels
baseline Duke index
baseline Gensini Score
case control
Liu, [25]
Golden Gate assay with an Illumina Bead Station 500 G system (Illumina, San Diego, Calif)
846 (−−/--%/whites)
Recurrent MI
Prospective cohort
rs2383207: chromosom
e 9
positions 21,930,588
Wang, [26]
TaqMan SNP allelic discrimination by means of an ABI 7900HT (Applied Biosystems, Foster City, CA, USA)
430 (−−/--%/Chinese)
no. new lesions
case control
Ardissino, [27]
Matrixassisted laser desorption ionization time-of-flight mass spectrometry and a Sequenome MassARRAY platform (San Diego, California)
1508 (41/95%/Italian)
All-cause mortality
recurrent MI
Prospective cohort
Wang, [28]
TaqMan SNP allelic discrimination by means of an ABI 7900HT (Applied Biosystems, Foster City, CA, USA)
rs1333049: 9p21.3
620 (67/51.2%/Chinese)
No. diseased vessels
baseline Gensini score
Cross sectional
Chan, [29]
332 (59/84%/whites)
no. new lesions
Prospective cohort
Dutta, [30]
Conventional Taqman PCR (probes and assays designed by Applied Biosystems; Foster City, CA)
478 (75/--%/whites)
All-cause mortality
Propective cohort
Kozieradzka, [31]
TaqMan SNP Genotyping Assay using the ABI 7500 Real Time PC R System (Applied Biosystems)
582 (62/75%/--)
All-cause mortality
Cohort Study
Gioli-Pereira, [32]
Submicroliter PCR-based assay on array tape that is a continuous plastic tape used in conjunction with a flexible configuration of dispensing, pipetting, sealing and detection modules manufactured by Douglas Global Array
rs10757274, rs2383206, rs10757278, rs1333049
rs10757274: 0.51,
611 (60/84.9%/Brazilian)
All-cause mortality
No. diseased vessels
Prospective cohort
rs2383206: 0.59,
rs10757278: 0.51,
rs1333049: 0.48
Virani, (1) [33]
TaqMan assays
CC: 0.27,
all 4 SNPs from our analyses (rs1333049, rs2383206, rs10757278, and rs10757274) have been shown to be in strong linkage disequilibrium (LD),
2067 (63/74%/whites)
All-cause mortality
recurrent MI
Prospective cohort
CG: 0.50,
GG: 0.23;
CABG group:
rs10757278, rs10757274
Virani, (2) [33]
TaqMan assays
CC: 0.30,
all 4 SNPs from our analyses (rs1333049, rs2383206, rs10757278, and rs10757274) have been shown to be in strong linkage disequilibrium (LD),
1176 (65/79%/whites)
All-cause mortality
recurrent MI
Prospective cohort
rs10757278, rs10757274
CG: 0.50,
GG: 0.21;
Lill, [34]   rs2383206     452 (58/78%/--) CAD All-cause mortality     Cohort Study

CAD: coronary artery disease; ACS: acute coronary syndrome; SCD: sickle-cell disease; MI: myocardial Infarction.

[TableWrap ID: T2] Table 2 

Pooled statistics using additive [LR vs. IR vs. HR], dominant [(LR + IR) vs. HR)], and recessive [LR vs. (IR + HR)] models

  Number of cohorts Number of patients RR 95% CI P value I2
Recurrent MI
Triple vessel disease
95% CI
Gensini Score
No. new lesions 2 293 0.03 −0.05 0.10 0.49 0.0%

MI indicates myocardial infarction; DPI, Duke CAD prognostic index; ∆MLD, change in minimum lumen diameter; No. new lesions, number of new lesions.

Article Categories:
  • Research Article

Keywords: Coronary, Atherosclerosis, 9p21-3.

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