A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction

Helgadóttir, Anna; Þorleifsson, Guðmar; Manolescu, Andrei; Grétarsdóttir, Sólveig; Blöndal, Thórarinn; Jónasdóttir, Áslaug; Jónasdóttir, Aðalbjörg; Sigurðsson, Ásgeir; Baker, Adam; Pálsson, Arnar; Másson, Gísli; Guðbjartsson, Daníel F.; Magnússon, Kristinn P.; Andersen, Karl; Levey, Aĺlan I.; Backman, Valgerdur M; Matthiasdottir, Sigurborg; Jónsdóttir, Þorbjörg; Palsson, Stefan; Einarsdóttir, Hildur; Gunnarsdóttir, Steinunn; Gylfason, Arnaldur; Vaccarino, Viola; Hooper, W. Craig; Reilly, Muredach P.; Granger, Christopher B.; Austin, Harland; Rader, Daniel J.; Shah, Svati H.; Quyyumi, Arshed A.; Gulcher, Jeffrey R.; Þorgeirsson, Guðmundur; Þorsteinsdóttir, Unnur; Kong, Augustine; Stefánsson, Kári

doi:10.1126/science.1142842

Cited by 1,434 publications

(651 citation statements)

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“…The association for the GRS and higher odds of MI was consistent with previous literature analyzing SNPs in the chromosome 9p21 and higher risk of CHD and mortality 6, 10, 12. Moreover, we observed that participants with the highest genetic risk in combination with the highest lifestyle risk factors (both all‐together as well as individually) had higher odds of MI.…”

Section: Discussionsupporting

confidence: 92%

“…Although the genetic variants used in the GRS have been associated with increased risk of CHD in European populations,6, 10, 12 they account for a modest portion of the variability in MI, and other genetic variants (for example, in genes of the inflammation response) could have a stronger effect in this population. A more comprehensive evaluation of gene–environment interactions with genetic markers in additional loci warrants future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to lifestyle, compelling evidence indicates that genetic susceptibility alone is part of the etiology of CHD and heart‐related events 6, 7, 8, 9, 10, 11. Genome‐wide association studies have identified chromosomal regions and genetic variants associated with CHD 6, 10, 12.…”

Section: Introductionmentioning

confidence: 99%

“…Genome‐wide association studies have identified chromosomal regions and genetic variants associated with CHD 6, 10, 12. One of the most robust genetic associations for CHD is the chromosome 9p21 region.…”

Section: Introductionmentioning

confidence: 99%

“…One of the most robust genetic associations for CHD is the chromosome 9p21 region. Several single nucleotide polymorphisms (SNPs) in this region have been associated with increased risk of CHD,6, 10, 12 such as a common sequence variant adjacent to genes CDKN2A and CDKN2B found to be associated with 1.64 times higher risk of MI 10. Recently, we showed that genetic markers in these loci were also associated with this outcome in the same MI case–control study of Costa Rican adults, when analyzed as part of a genetic risk score (GRS) 13.…”

Section: Introductionmentioning

confidence: 99%

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Lifestyle Cardiovascular Risk Score, Genetic Risk Score, and Myocardial Infarction in Hispanic/Latino Adults Living in Costa Rica

Sotos‐Prieto

Baylin

Campos

et al. 2016

JAHA

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BackgroundA lifestyle cardiovascular risk score (LCRS) and a genetic risk score (GRS) have been independently associated with myocardial infarction (MI) in Hispanics/Latinos. Interaction or joint association between these scores has not been examined. Thus, our aim was to assess interactive and joint associations between LCRS and GRS, and each individual lifestyle risk factor, on likelihood of MI.Methods and ResultsData included 1534 Costa Rican adults with nonfatal acute MI and 1534 matched controls. The LCRS used estimated coefficients as weights for each factor: unhealthy diet, physical inactivity, smoking, elevated waist:hip ratio, low/high alcohol intake, low socioeconomic status. The GRS included 14 MI‐associated risk alleles. Conditional logistic regressions were used to calculate adjusted odds ratios. The odds ratios for MI were 2.72 (2.33, 3.17) per LCRS unit and 1.13 (95% CI 1.06, 1.21) per GRS unit. A significant joint association for highest GRS tertile and highest LCRS tertile and odds of MI was detected (odds ratio=5.43 [3.71, 7.94]; P<1.00×10−7), compared to both lowest tertiles. The odds ratios were 1.74 (1.22, 2.49) under optimal lifestyle and unfavorable genetic profile, and 5.02 (3.46, 7.29) under unhealthy lifestyle but advantageous genetic profile. Significant joint associations were observed for the highest GRS tertile and the highest of each lifestyle component risk category. The interaction term was nonsignificant (P=0.33).ConclusionsLifestyle risk factors and genetics are jointly associated with higher odds of MI among Hispanics/Latinos. Individual and combined lifestyle risk factors showed stronger associations. Efforts to improve lifestyle behaviors could help prevent MI regardless of genetic susceptibility.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Lifestyle Cardiovascular Risk Score, Genetic Risk Score, and Myocardial Infarction in Hispanic/Latino Adults Living in Costa Rica

Sotos‐Prieto

Baylin

Campos

et al. 2016

JAHA

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Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes

Doria

Wójcik

et al. 2008

JAMA

118

100

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Context A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease (CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized. Objective To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control. Design, Setting, and Participants 1. Case-control study of 734 type 2 diabetic patients (322 with angiographically-diagnosed CAD and 412 with no evidence of CAD) who were recruited in 2001–2006 at the Joslin Clinic/Beth Israel Deaconess Medical Center, 2. Independent cohort study of 475 type 2 diabetic patients from the Joslin Clinic whose survival status was monitored from their recruitment in 1993–1996 until December 31, 2004. Study subjects were genotyped for a representative SNP at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A1c (HbA1c) measurements taken in the years before study entry. Main Outcome Measures Case-control study: association between SNP rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof. Cohort study: cumulative 10-year mortality. Results Individuals homozygous for the risk allele were significantly more frequent in case than control subjects (42.3 vs. 28.9%, p=0.0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted p for interaction = 0.048) in the presence of poor glycemic control (worst tertile of the distribution of HbA1c at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD risk for subjects having two risk alleles but not poor glycemic control was increased two-fold (OR=1.99, 1.17–3.41), whereas the risk for study subjects with the same genotype and with poor glycemic control was increased four-fold (OR=4.27, 2.26–8.01). The interaction was stronger (adjusted p=0.005) when a measure of long-term glycemic control (7-year average rather than most recent HbA1c) was used, with ORs of 7.83 (3.49–17.6) for subjects having two risk alleles and a history of poor glycemia and 1.54 (0.72–3.30) for subjects with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10-year mortality in the cohort study (43.6% in patients with two risk alleles and poor glycemic control, 23.1% in those with only the two risk alleles, 30.0% in those with only poor glycemic control, and 31.6% in those with neither factor, p for interaction=0.036). Conclusions In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes.

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Association Between 9p21 Genomic Markers and Heart Disease

Palomaki

Melillo²,

Bradley³

2010

JAMA

152

107

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REVENTING AND MANAGING CARdiovascular disease (CVD) presents a challenge for health care and public health. 1,2 Nonmodifiable risk factors include increasing age, male sex, and heredity. Modifiable risk factors include smoking, hypertension, dyslipidemia, obesity, physical inactivity, and diabetes. [3][4][5] Among men, the annual rate of initial CVD events increases from 3 to 74 per 1000 from ages 35 to 44 years to ages 85 to 94 years, respectively. Similar increases occur among women a decade later. 6 Biomarkers (eg, C-reactive protein) have been combined with traditional risk factors to predict CVD events, 7 and molecular markers hold further promise. In 2007, genome-wide association studies on CVD identified a series of associated singlenucleotide polymorphisms (SNPs) in an intergenic region of chromosome 9p21, near the CDKN2A (NM_000077) and CDKN2B (NM_004936) genes. 8,9 Currently, no comprehensive compilation of the 9p21 literature uses formal methods to estimate the strength of the association with heart disease (eg, effect size, heterogeneity, publication bias, credibility of cumulative evidence) and examine clinical utility. This analysis is part of a targeted systematic review on existing cardiogenomic panels that in-cluded 28 genes in addition to the 9p21 SNPs. That review was commissioned by the Evaluation of Genomic Applica-

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A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction

Cited by 1,434 publications

References 8 publications

Lifestyle Cardiovascular Risk Score, Genetic Risk Score, and Myocardial Infarction in Hispanic/Latino Adults Living in Costa Rica

Lifestyle Cardiovascular Risk Score, Genetic Risk Score, and Myocardial Infarction in Hispanic/Latino Adults Living in Costa Rica

Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes

Association Between 9p21 Genomic Markers and Heart Disease

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