Gene Mapping of Susceptibility to Periodontitis

大量证据表明，个体之间的遗传差异对慢性牙周炎的风险有主要影响。然而，这种疾病很可能具有复杂的病因，多个基因的遗传变异与吸烟、卫生、接触病原体等环境因素相互作用，从而决定个体的疾病风险。我们对成年双胞胎的研究表明，通过定量测量，如平均附着丧失（AL）和AL大于2毫米、3毫米或4毫米阈值的位点百分比，遗传率为50%或更高。我们对早发性侵袭性牙周炎家族的基因定位分析已经确定了数十个候选基因，这些基因在这种疾病亚型中具有很强到中等程度的支持。我们最近也表明牙周炎相关表型如血清免疫球蛋白水平具有高度显著的遗传性。用于分析单核苷酸多态性（snp）的人类分子基因组学技术和统计遗传策略（如单倍型定位）的重大进展可能极大地提高了识别复杂性状（如牙周炎）的基因的能力。这种方法成功所需的一个关键组成部分是获得非常大的、高质量的临床人群。我们建议应用这些工具和方法，通过测试100多个与牙周炎相关的候选基因中的500多个snp，来推进对慢性牙周炎易感性的遗传和环境基础的理解。从NHANES III研究中获得DNA的7300名受试者；二)。在明尼苏达州招募了200名患有严重慢性牙周炎的成年受试者和100名健康对照者；iii.)我们先前报道的双胞胎研究中显示慢性牙周炎高遗传性的234名受试者；Iv)通过评估这些临床人群的替代定量和疾病分类（离散）措施；v)通过分析所有样本中的环境危险因素和NHANES样本中对牙周病原体的抗体反应。

DESCRIPTION: Substantial evidence indicates that genetic differences among individuals have a major effect on risk of chronic periodontitis. It is very likely this disease has a complex etiology, however, with inherited variation at multiple genes interacting with environmental factors such as smoking, hygiene, exposure to pathogens to determine individuals' disease risk. Our studies of adult twins demonstrated heritability of 50% and higher for quantitative measures such as mean attachment loss (AL) and percentage of sites with AL greater than thresholds of 2 mm, 3 mm or 4 mm. Our gene mapping analyses of early onset aggressive periodontitis families have identified dozens of candidate genes with strong to moderate support for involvement in this disease subtype. We have also recently shown that periodontitis-related phenotypes such as serum immunoglobulin levels have highly significant heritability. Major advances in human molecular genomics techniques for analysis of single nucleotide polymorphisms (SNPs) and statistical genetic strategies such as haplotype mapping may provide greatly increased power to identify genes underlying complex traits such as periodontitis. A critical component needed for success in this approach is availability of very large, high quality clinical populations. We propose to apply these tools and approaches to advance understanding of the genetic and environmental basis of susceptibility to chronic periodontitis by testing over 500 SNPs in over 100 candidate genes for association with periodontitis in i.) 7,300 subjects from the NHANES III study for whom DNA is available; ii.) 200 adult subjects with severe chronic periodontitis and 100 healthy controls recruited in Minnesota; and iii.) in 234 subjects from our previously reported twin study that demonstrated high heritability of chronic periodontitis; iv) by evaluating alternative quantitative and disease classification (discrete) measures in these clinical populations; and v.) by analyzing environmental risk factors in all samples and antibody responses to periodontal pathogens in the NHANES sample.