Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis

Arne S. Schaefer*, Gregor Bochenek, Arne Jochens, David Ellinghaus, Henrik Dommisch, Esra Güzeldemir-Akҫakanat, Christian Graetz, Inga Harks, Yvonne Jockel-Schneider, Knut Weinspach, Joerg Meyle, Peter Eickholz, Gerry J. Linden, Naci Cine, Rahime Nohutcu, Ervin Weiss, Yael Houri-Haddad, Fuad Iraqi, Mathias Folwaczny, Barbara NoackKonstantin Strauch, Christian Gieger, Melanie Waldenberger, Annette Peters, Cisca Wijmenga, Engin Yilmaz, Wolfgang Lieb, Philip Rosenstiel, Christof Doerfer, Corinna Bruckmann, Jeannette Erdmann, Inke König, Søren Jepsen, Bruno G. Loos, Stefan Schreiber

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background - Genetic studies demonstrated the presence of risk alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between coronary artery disease (CAD) and periodontitis. We aimed to identify further shared genetic risk factors to better understand conjoint disease mechanisms. Methods and Results - In-depth genotyping of 46 published CAD risk loci of genome-wide significance in the worldwide largest case-control sample of the severe early-onset phenotype aggressive periodontitis (AgP) with the Illumina Immunochip (600 German AgP cases, 1448 controls) and the Affymetrix 500K array set (283 German AgP cases and 972 controls) highlighted ANRIL as the major risk gene and revealed further associations with AgP for the gene PLASMINOGEN (PLG; rs4252120: P=5.9×10-5; odds ratio, 1.27; 95% confidence interval, 1.3-1.4 [adjusted for smoking and sex]; 818 cases; 5309 controls). Subsequent combined analyses of several genome-wide data sets of CAD and AgP suggested TGFBRAP1 to be associated with AgP (rs2679895: P=0.0016; odds ratio, 1.27 [95% confidence interval, 1.1-1.5]; 703 cases; 2.143 controls) and CAD (P=0.0003; odds ratio, 0.84 [95% confidence interval, 0.8-0.9]; n=4117 cases; 5824 controls). The study further provides evidence that in addition to PLG, the currently known shared susceptibility loci of CAD and periodontitis, ANRIL and CAMTA1/VAMP3, are subjected to transforming growth factor-β regulation. Conclusions - PLG is the third replicated shared genetic risk factor of atherosclerosis and periodontitis. All known shared risk genes of CAD and periodontitis are members of transforming growth factor-β signaling.

Original languageEnglish
Pages (from-to)159-167
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number1
DOIs
StatePublished - 4 Feb 2015

Keywords

  • coronary artery disease
  • genetic association studies
  • periodontitis
  • plasminogen

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