Munz Matthias, Willenborg Christina, Richter Gesa M, Jockel-Schneider Yvonne, Graetz Christian, Staufenbiel Ingmar, Wellmann Jürgen, Berger Klaus, Krone Bastian, Hoffmann Per, van der Velde Nathalie, Uitterlinden André G, de Groot Lisette C P G M, Sawalha Amr H, Direskeneli Haner, Saruhan-Direskeneli Güher, Guzeldemir-Akcakanat Esra, Keceli Huseyin Gencay, Laudes Matthias, Noack Barbara, Teumer Alexander, Holtfreter Birte, Kocher Thomas, Eickholz Peter, Meyle Jörg, Doerfer Christof, Bruckmann Corinna, Lieb Wolfgang, Franke Andre, Schreiber Stefan, Nohutcu Rahime M, Erdmann Jeanette, Loos Bruno G, Jepsen Soeren, Dommisch Henrik, Schaefer Arne S
Department of Periodontology and Synoptic Dentistry, Institute of Dental, Oral and Maxillary Medicine, Charité - University Medicine Berlin, Germany.
Institute for Integrative and Experimental Genomics, University Medical Center Schleswig-Holstein - Campus Lübeck, Germany.
Hum Mol Genet. 2017 Jul 1;26(13):2577-2588. doi: 10.1093/hmg/ddx151.
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.
牙周炎是最常见的炎症性疾病之一，全球严重形式的患病率为11%，估计遗传度为50%。该疾病的特征是由于宿主对功能失调的口腔微生物群产生异常炎症反应，导致牙槽骨破坏。以往的全基因组关联研究（GWAS）报告了几个提示性的易感位点。在这里，我们使用德国和荷兰侵袭性牙周炎（AgP，896例病例，7104例对照）的病例对照样本进行了GWAS，侵袭性牙周炎是一种罕见但非常严重且发病早的牙周炎形式，并在德国更中度表型慢性牙周炎（CP）（993例病例，1419例对照）的严重形式样本中验证了这些关联。在土耳其AgP样本（223例病例，564例对照）中重复了阳性结果。SIGLEC5（唾液酸结合免疫球蛋白样凝集素5）位点和DEFA1A3位点（防御素α1-3）下游的一个染色体区域与两种疾病表型均相关，并且在合并样本中与牙周炎的关联达到全基因组显著性水平，P分别为1.09E-08（rs4284742，-G；OR = 1.34，95% CI = 1.21-1.48）和5.48E-10（rs2738058，-T；OR = 1.28，95% CI = 1.18-1.38）。SIGLEC5在各种髓系免疫细胞中表达，被归类为一种抑制性受体，具有介导酪氨酸磷酸酶SHP-1/-2依赖性信号传导的潜力。α-防御素是抗菌肽，在中性粒细胞和黏膜表面表达，在吞噬细胞介导的宿主防御中起作用。本研究确定了具有全基因组显著性的AgP和CP的首个共同遗传风险位点，并强调了先天免疫和适应性免疫在牙周炎病因学中的作用。
