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Jessica Kristin Henes,1,* Patrick Groga-Bada,1,* Elke Schaeffeler,2,3 Stefan Winter,2,3 Luis Hack,1 Monika Zdanyte,1 Karin Mueller,1 Michal Droppa,1 Fabian Stimpfle,1 Meinrad Gawaz,1 Harald Langer,4 Matthias Schwab,2,3,5,6 Tobias Geisler,1 Dominik Rath1 1Department of Cardiology, University Hospital Tuebingen, Tuebingen, Germany; 2Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; 3University of Tuebingen, Tuebingen, Germany; 4Department of Cardiology, Angiology and Intensive Care, University Hospital Luebeck, Luebeck, Germany; 5Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany; 6Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany*These authors contributed equally to this workCorrespondence: Tobias GeislerMedizinische Klinik III, Department Cardiology and Cardiovascular Research, Otfried-Müller-Strasse 10, Tübingen, 72076 Tel +49 7071/29-8 36 88Fax +49 7071/29-57 49Email tobias.geisler@med.uni-tuebingen.deBackground: Complement component 5a (C5a) is a highly potent anaphylatoxin with a variety of pro-inflammatory effects. C5a contributes to progression of atherosclerosis and inhibition of the receptor (C5aR) might offer a therapeutic strategy in this regard. Single nucleotide polymorphisms (SNPs) of the C5 gene may modify protein expression levels and therefore function of C5a and C5aR. This study aimed to examine associations between clinically relevant C5a SNPs and the prognosis of patients with symptomatic coronary artery disease (CAD). Furthermore, we sought to investigate the influence of C5 SNPs on C5aR platelet surface expression and circulating C5a levels.Methods: C5 variants (rs25681, rs17611, rs17216529, rs12237774, rs41258306, and rs10985126) were analyzed in a consecutive cohort of 833 patients suffering from symptomatic coronary artery disease (CAD). Circulating C5a levels were determined in 116 patients whereas C5aR platelet surface expression was measured in 473 CAD patients. Endpoints included all-cause mortality, myocardial infarction (MI), and ischemic stroke (IS). Homozygous carriers (HC) of the minor allele (rs10985126) showed significantly higher all-cause mortality than major allele carriers. While we could not find significant associations between rs10985126 allele frequency and C5aR platelet surfazl ce expression, significantly elevated levels of circulating C5a were found in HC of the minor allele of the respective genotype. rs17216529 allele frequency correlated with the composite combined endpoint and bleeding events. However, since the number of HC of the minor allele of this genotype was low, we cannot draw a robust conclusion about the observed associations.Conclusion: In this study, we provide evidence for the prognostic relevance of rs10985126 in CAD patients. C5 rs10985126 may serve as a prognostic biomarker for risk stratification in high-risk CAD patients and consequently promote tailored therapies.Keywords: coronary artery disease, SNPs, complement C5, prognostic factors