Offenbacher Steven, Divaris Kimon, Barros Silvana P, Moss Kevin L, Marchesan Julie T, Morelli Thiago, Zhang Shaoping, Kim Steven, Sun Lu, Beck James D, Laudes Matthias, Munz Matthias, Schaefer Arne S, North Kari E
Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
Department of Pediatric Dentistry, UNC School of Dentistry, Chapel Hill, NC, USA Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
Hum Mol Genet. 2016 May 15;25(10):2113-2129. doi: 10.1093/hmg/ddw069. Epub 2016 Mar 8.
Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.
仅依据临床标准对慢性牙周炎（CP）开展的全基因组关联研究（GWAS），迄今为止成效有限。在此，我们通过补充微生物负荷（8种牙周病原体水平）和局部炎症反应（龈沟液白细胞介素-1β）的生物学中间指标来细化CP表型，并通过主成分分析得出牙周复合性状（PCT）。将PCT应用于GWAS（约250万个标记），以在“牙科社区动脉粥样硬化风险研究（Dental ARIC study）”的975名欧美成年参与者中识别与PCT相关的基因座。我们试图在更大规模的ARIC队列（821名重度CP参与者、2031名中度CP参与者、1914名健康/轻度疾病参与者）以及一个包含717例侵袭性牙周炎病例和4210名对照的独立德国样本中验证这些CP研究结果。我们识别出6种具有不同微生物群落/白细胞介素-1β结构的PCT，尽管它们的临床表现存在重叠。PCT1的特征是病原体负荷普遍较高，而PCT3和PCT5分别以伴放线聚集杆菌和牙龈卟啉单胞菌为主。我们检测到PCT1（CLEC19A、TRA、GGTA2P、TM9SF2、IFI16、RBMS3）、PCT4（HPVC1）和PCT5（SLC15A4、PKP2、SNRPN）存在全基因组显著信号。总体而言，所突出的基因座包括与免疫反应和上皮屏障功能相关的基因。除了BEGAIN与重度CP以及UBE3D与中度CP的关联外，在ARIC队列中没有其他基因座与CP相关，在德国样本中也没有基因座与侵袭性牙周炎相关。尽管这些基因座与当前临床确定的牙周疾病分类无关，但经过重复验证和机制验证后，这些候选基因座可能会凸显CP生物学亚型潜在的生态失调微生物群落结构以及改变的炎症/免疫反应。
