Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21–1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18–1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of 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, 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.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10⁻⁹, OR = 1.36, 95% CI = [1.23–1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10⁻⁹, OR = 1.24, 95% CI = [1.15–1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.

Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (P_AgP-Ger < 0.05; P_CAD < 5 × 10⁻⁸; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02–1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05–1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.