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

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, 1,448 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), OR=1.27, 95% CI=1.3-1.4 [adjusted for smoking and sex]; 818 cases, 5,309 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, OR=1.27 [95% CI=1.1-1.5]; 703 cases, 2.143 controls) and CAD (P=0.0003, OR=0.84 [95% CI=0.8-0.9]; N=4,117 cases, 5,824 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 TGF-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 TGF-β signaling