Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System

Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E Kleber, Winfried März, Christoph Sinning, Fabian J Brunner, Christoph Waldeyer, Till Keller, Christoph H Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel, Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E Kleber, Winfried März, Christoph Sinning, Fabian J Brunner, Christoph Waldeyer, Till Keller, Christoph H Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel

Abstract

Coronary artery disease (CAD) has a complex etiology involving numerous environmental and genetic factors of disease risk. To date, the genetic 9p21 locus represents the most robust genetic finding for prevalent and incident CAD. However, limited information is available on the genetic background of the severity and distribution of CAD. CAD manifests itself as stable CAD or acute coronary syndrome. The Gensini score quantifies the extent CAD but requires coronary angiography. Here, we aimed to identify novel genetic variants associated with Gensini score severity and distribution of CAD. A two-stage approach including a discovery and a replication stage was used to assess genetic variants. In the discovery phase, a meta-analysis of genome-wide association data of 4,930 CAD-subjects assessed by the Gensini score was performed. Selected single nucleotide polymorphisms (SNPs) were replicated in 2,283 CAD-subjects by de novo genotyping. We identified genetic loci located on chromosome 2 and 9 to be associated with Gensini score severity and distribution of CAD in the discovery stage. Although the loci on chromosome 2 could not be replicated in the second stage, the known CAD-locus on chromosome 9p21, represented by rs133349, was identified and, thus, was confirmed as risk locus for CAD severity.

Keywords: Gensini score; genetics; genome-wide association; polymorphism; severity of coronary artery disease.

Figures

Figure 1
Figure 1
Manhattan Plot of −log10 (p) for association of single nucleotide polymorphisms (SNPs) and chromosomal position for all autosomal SNPs analyzed in the meta-analysis of three independent discovery cohorts. Associations with a p–value <5 × 10−8 were considered genome-wide significant. The analysis was adjusted for age and gender.
Figure 2
Figure 2
Forest plots showing the results of the association analyses for each single study in the discovery (upper panel) and replication (lower panel) phase and for the meta-analysis are presented. The effect estimates and 95% confidence intervals are provided for each study separately and in combined analysis.

References

    1. McPherson R, Tybjaerg-Hansen A. Genetics of coronary artery disease. Circ Res (2016) 118:564–78.10.1161/CIRCRESAHA.115.306566
    1. Kessler T, Erdmann J, Schunkert H. Genetics of coronary artery disease and myocardial infarction – 2013. Curr Cardiol Rep (2013) 15:368.10.1007/s11886-013-0368-0
    1. Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet (2015) 47:1121–30.10.1038/ng.3396
    1. Wilson PW, D’agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation (1998) 97:1837–47.10.1161/01.CIR.97.18.1837
    1. Yeboah J, Mcclelland RL, Polonsky TS, Burke GL, Sibley CT, O’leary D, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA (2012) 308:788–95.10.1001/jama.2012.9624
    1. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J (2013) 34:2949–3003.10.1093/eurheartj/eht296
    1. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol (1983) 51:606.10.1016/S0002-9149(83)80105-2
    1. Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G, Tiret L, et al. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med (2003) 349:1605–13.10.1056/NEJMoa030535
    1. Beutner F, Teupser D, Gielen S, Holdt LM, Scholz M, Boudriot E, et al. Rationale and design of the Leipzig (LIFE) Heart Study: phenotyping and cardiovascular characteristics of patients with coronary artery disease. PLoS One (2011) 6:e29070.10.1371/journal.pone.0029070
    1. Winkelmann BR, Marz W, Boehm BO, Zotz R, Hager J, Hellstern P, et al. Rationale and design of the LURIC study – a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics (2001) 2:S1–73.10.1517/14622416.2.1.S1
    1. Sinning C, Lillpopp L, Appelbaum S, Ojeda F, Zeller T, Schnabel R, et al. Angiographic score assessment improves cardiovascular risk prediction: the clinical value of SYNTAX and Gensini application. Clin Res Cardiol (2013) 102:495–503.10.1007/s00392-013-0555-4
    1. Diemert P, Schunkert H. Genomic reflections of coronary artery disease. Circ Cardiovasc Genet (2011) 4:7–8.10.1161/CIRCGENETICS.110.959163
    1. Fischer M, Broeckel U, Holmer S, Baessler A, Hengstenberg C, Mayer B, et al. Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction. Circulation (2005) 111:855–62.10.1161/
    1. Dandona S, Stewart AF, Chen L, Williams K, So D, O’brien E, et al. Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol (2010) 56:479–86.10.1016/j.jacc.2009.10.092
    1. Patel RS, Su S, Neeland IJ, Ahuja A, Veledar E, Zhao J, et al. The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease. Eur Heart J (2010) 31:3017–23.10.1093/eurheartj/ehq272
    1. Rivera NV, Carreras-Torres R, Roncarati R, Viviani-Anselmi C, De Micco F, Mezzelani A, et al. Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes. BMC Med Genet (2013) 14:11.10.1186/1471-2350-14-11
    1. Cakmak HA, Bayoglu B, Durmaz E, Can G, Karadag B, Cengiz M, et al. Evaluation of association between common genetic variants on chromosome 9p21 and coronary artery disease in Turkish population. Anatol J Cardiol (2015) 15:196–203.10.5152/akd.2014.5285
    1. Jing J, Su L, Zeng Y, Tang X, Wei J, Wang L, et al. Variants in 9p21 predicts severity of coronary artery disease in a Chinese han population. Ann Hum Genet (2016) 80:274–81.10.1111/ahg.12163
    1. Anderson JL, Horne BD, Kolek MJ, Muhlestein JB, Mower CP, Park JJ, et al. Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility. Am Heart J (2008) 156(1155–1162):e1152.10.1016/j.ahj.2008.07.006
    1. Chen SN, Ballantyne CM, Gotto AM, Jr, Marian AJ. The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis. BMC Cardiovasc Disord (2009) 9:3.10.1186/1471-2261-9-3
    1. Chan K, Patel RS, Newcombe P, Nelson CP, Qasim A, Epstein SE, et al. Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis. J Am Coll Cardiol (2013) 61:957–70.10.1016/j.jacc.2012.10.051

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться