Aggressive Periodontitis and Formylpeptide Receptor SNPs

描述（由申请人提供）：甲酰基肽受体（FPR）在帮助多形核白细胞（PMN）定位和中和细菌感染方面发挥重要作用。FPR表达和PMN趋化性缺陷在侵袭性牙周炎（AP）患者中很常见，AP是一种导致严重、快速牙周破坏的疾病。AP在非裔美国人中最为普遍，并表现出家族聚集性。我们的研究表明，AP与编码FPR的基因中的沉默单核苷酸多态性（SNP） C . 348t >C有关。在非裔美国人中，348T等位基因在AP患者中的出现频率高于健康对照（P = 0.001）。我们假设348T与FPR基因启动子中的一个或多个snp相关联，这可能导致FPR表达受损，并增加发生AP的风险。p2-肾上腺素能受体基因中也存在类似的沉默编码snp与启动子snp的连锁。本项目将探讨非洲裔美国人FPR snp、FPR表达缺陷、趋化性缺陷与AP易感性之间的关系。在Specific Aim 1中，将克隆一个FPR基因片段并对其进行测序，以表征：a) C . 348t >C（以及FPR编码区域的其他个体和连锁snp）与AP的关联，b) C . 348t >C与FPR启动子区域snp的关联。在Specific Aim 2中，将表征C . 348t >C与PMN趋化性缺陷和FPR表达的关系。如果这些研究证实了我们的假设，它们将为在分子水平上解释为什么C . 348t b> C与FPR表达缺陷相关的研究奠定基础，并为更大规模的临床研究提供理由，以开发检测AP易感个体的方法。如果有有效的易感指标可用，那么对于存在病原体的年轻非洲裔美国人来说，检测AP风险增加是明智的。在AP临床表达之前进行有针对性的治疗干预，消除病原体，可以减轻牙周破坏，最大限度地减少与牙齿脱落相关的功能和美观问题，并降低牙科护理成本。

DESCRIPTION (provided by applicant): Formylpeptide receptors (FPR) play an important role in helping polymorphonuclear leukocytes (PMN) locate and neutralize bacterial infections. Defects in FPR expression and PMN chemotaxis are common in patients with aggressive periodontitis (AP), a disorder that produces severe, rapid periodontal destruction. AP is most prevalent in African-Americans and exhibits a familial aggregation. Our studies show that AP is associated with the silent single nucleotide polymorphism (SNP) c.348T>C in the gene that encodes FPR. In African-Americans, the 348T allele occurs at a higher frequency in individuals with AP than in healthy controls (P = 0.001). We hypothesize that 348T is linked to one or more SNPs in the FPR gene promoter, which could contribute to impaired FPR expression and increased risk of developing AP. An analogous linkage of silent coding SNPs with promoter SNPs exists in the p2-adrenergic receptor gene. This project will explore the relationship between FPR SNPs, FPR expression defects, chemotaxis defects and susceptibility to AP in African-Americans. In Specific Aim 1, an FPR gene fragment will be cloned and sequenced to characterize: a) the association of c.348T>C (and other individual and linked SNPs in the FPR coding region) with AP, and b) the association of c.348T>C with SNPs in the FPR promoter region. In Specific Aim 2, the relationship of c.348T>C to defects in PMN chemotaxis and FPR expression will be characterized. If these studies confirm our hypothesis, they will lay the foundation for studies that will explain at the molecular level why c.348T>C is associated with defective FPR expression and justify a larger clinical study to develop methods to detect individuals susceptible to AP. If a valid indicator of susceptibility were available, it would be prudent to test young African-Americans who are at increased risk of developing AP for the presence of pathogens. Targeted therapeutic intervention to eliminate pathogens prior to clinical expression of AP could mitigate periodontal destruction, minimize functional and esthetic problems related to tooth loss, and reduce the cost of dental care.