Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus

Abstract

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 (PAgP-Ger < 0.05; PCAD < 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.

Genomics of periodontal disease and tooth morbidity

“…There was suggestive evidence of an association in a North American genome‐wide association study of chronic periodontitis and it was the locus with the strongest evidence of association in a German male‐only stratified sample of aggressive periodontitis . Additional genome areas with multiple, independent genome‐wide association level of evidence, albeit not reaching genome‐wide significance or formal genome‐wide replication, include ANRIL , CAMTA1/VAMP3 , PF4 / PPBP / CXCL5 , NIN / CDKL1 , PLG , VAMP8 (rs1561198), MTND1P5 (rs16870060), and LOC107984137/ SHISA9 (rs729876) . A gene‐centric and gene set enrichment re‐analysis of our group's single‐marker genome‐wide association study of chronic periodontitis and periodontal pathogen colonization has also been reported, including variable definitions of “gene boundaries” .…”

“…However, two loci showed evidence of a statistically significant genome-wide association in subsequent gene-centric re-analyses (KCNK1, P = 3.4 × 10 −7 for high "red complex" colonization and DAB2IP, P = 1.0 × 10 −6 for Porphyromonas gingivalis high colonization). 45 Moreover, three single nucleotide polymorphisms initially prioritized (P < 5 × 10 −6 ) by our genomewide association study of periodontitis (rs2521634; NPY locus) 27 and periodontal pathogen colonization (rs10010758; TBC1D1 locus and rs10043775; FBXO30 locus) 32 were subsequently found to be associated with periodontal pathogen colonization by a recent independent study by Cavalla et al 91 Specifically, the NPY locus was associated with Tannerella forsythia, Actinomyces gerencseriae, Fusobacterium periodonticum, and Prevotella nigrescens colonization, the TBC1D1 locus with P. gingivalis, and the FBXO30 locus with Prevotella intermedia, after adjustment for multiple testing.…”

Periodontitis and cardiovascular diseases: Consensus report

“…There is scientific evidence of pleiotropy between periodontitis and cardiovascular diseases (Aarabi et al, ; Munz et al, ; Schaefer et al, , ). The highly pleiotropic genetic locus CDKN2B‐AS1 (chromosome 9, p21.3) associated with coronary artery disease, type 2 diabetes, ischaemic stroke and Alzheimer’s disease is also consistently associated with periodontitis (Aarabi et al, ; Ernst et al, ; Loos, Papantonopoulos, Jepsen, & Laine, ; Munz et al, ). Its function appears to be related to the regulation of gene expression (Hubberten et al, ).…”

Periodontitis and Cardiovascular Diseases. Consensus Report

“…There is scientific evidence of pleiotropy between periodontitis and cardiovascular diseases [1,83,111,112]. The highly pleiotropic genetic locus CDKN2B-AS1 (chromosome 9, p21.3) associated with coronary artery disease, type 2 diabetes, ischemic stroke and Alzheimer's disease is also consistently associated with periodontitis [1,33,68,83]. Its function appears to be related to the regulation of gene expression [48].…”

“…The fourth pleiotropic locus between coronary artery disease and periodontitis is a haplotype block at the VAMP8 locus [83].…”