Gene Mapping of Susceptibility to Periodontitis

描述：大量证据表明，个体间的遗传差异对患慢性牙周炎的风险有重要影响。然而，这种疾病很可能有复杂的病因，多个基因的遗传变异与环境因素相互作用，如吸烟、卫生、接触病原体等，以确定个人的疾病风险。我们对成年双胞胎的研究表明，平均依恋丧失(AL)和AL大于阈值2 mm、3 mm或4 mm的部位百分比等定量指标的遗传率为50%或更高。我们对早发性侵袭性牙周炎家系的基因图谱分析已经确定了数十个与这种疾病亚型有关的候选基因，这些基因具有强烈到中等的支持。我们最近还发现，与牙周炎相关的表型，如血清免疫球蛋白水平，具有非常显著的遗传力。人类分子基因组学技术在分析单核苷酸多态(SNPs)和统计遗传策略(如单倍型图谱)方面的重大进展可能会大大提高识别牙周炎等复杂特征的基因的能力。这一方法取得成功所需要的一个关键组成部分是拥有非常大的、高质量的临床人口。我们建议应用这些工具和方法，通过测试与牙周炎相关的100多个候选基因中的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。i)来自NHANES III研究的7,300名可获得DNA的受试者；ii.)200名患有严重慢性牙周炎的成年受试者和100名在明尼苏达州招募的健康对照组；以及3.)在我们先前报道的双胞胎研究中的234名受试者中，这些研究表明慢性牙周炎的遗传性很高；iv)通过评估这些临床人群中替代的量化和疾病分类(离散)措施；以及V.)通过分析所有样本中的环境风险因素和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.