IDENTIFICATION OF GENES PREDISPOSING TO PELVIC FLOOR DISORDERS

描述（由申请人提供）：研究人员提出了犹他州基础和临床科学家之间的独特和强大的合作，以确定影响盆腔器官脱垂（POP）易感性的基因。共同PI都有重要的经验，诺顿博士在骨盆底疾病（PFD）遗传学和加农奥尔布赖特博士在易感基因鉴定。研究人员将访问犹他州人口数据库，这是一个犹他州的计算机化家谱，结合了来自犹他州两个最大的医疗系统（服务于该州90%的人口）的数十年医疗数据，以确定和招募手术治疗的POP病例（5年内1,250例）。将使用Illumina 610 Q SNP标记集对所有采样的POP病例进行基因分型。PI将对基因分型的POP病例资源进行多种不同的遗传分析，以帮助识别易感基因。医疗程序代码（识别对每个患者进行的手术）与个人家谱数据的记录链接使我们能够识别POP病例之间的所有遗传关系。我们将使用我们开发的软件进行全基因组关联分析，该软件允许包括独立和相关病例。我们将确定抽样POP病例之间的所有遗传关系，并在信息丰富的高风险POP家系中进行连锁分析。我们将在这些家系中的远亲病例中确定遗传相同（IBD）的染色体区域，并将在一小部分POP病例（2%）中确定IBD共享。Norton博士的NIH资助的受影响PFD同胞研究获得的数据的初步合作分析已经为染色体臂9 q上的易感基因定位提供了重要证据，并为1号染色体上至少一个其他位点提供了暗示性证据。总之，我们将建立一个以人群为基础的手术治疗POP病例的资源，我们将采用现有的和新的方法来识别和定位影响POP的易感基因，我们将开始详细搜索我们已经定位的9号染色体基因。 公共卫生相关性：这项研究在预防PFDs方面具有影响公共卫生的重大潜力：我们可能能够识别高风险人群，这些人群可以在年轻时识别，研究并可能有针对性地进行预防;在PFDs发展的后期阶段，可以研究特殊干预措施，并可能在有复发风险的妇女中实施。总有一天，这些高危人群的识别可能会像家族风险一样普遍，或者像特定基因筛查一样具体。

DESCRIPTION (provided by applicant): The investigators propose a unique and powerful collaboration between basic and clinical scientists in Utah to identify genes affecting predisposition to pelvic organ prolapse (POP). The co-PIs both have significant experience, Dr. Norton in Pelvic Floor Disorder (PFD) genetics and Dr. Cannon-Albright in predisposition gene identification. The investigators will access the Utah Population Database, a computerized genealogy of Utah combined with decades of medical data from the two largest healthcare systems in Utah (serving 90% of the state), to identify and recruit surgically treated cases of POP (1,250 cases in 5 years). All POP cases sampled will be genotyped with the Illumina 610Q SNP marker set. The PIs will apply multiple different genetic analyses to this resource of genotyped POP cases to aid in the identification of predisposition genes. The record linkage of medical procedure codes (identifying surgeries performed on each patient) to individual genealogy data allows us to identify all genetic relationships among the POP cases. We will perform genome-wide association analysis, using software we have developed which allows inclusion of both independent and related cases. We will identify all genetic relationships between the sampled POP cases and perform linkage analysis in informative, high-risk POP pedigrees. We will identify chromosomal regions shared Identical by Descent (IBD) in very distantly related cases in these pedigrees, and we will identify IBD sharing within the small subset of POP cases (2%) who are inbred. Initial collaborative analysis of data obtained by Dr. Norton's NIH funded study of affected PFD sib-ships has already provided significant evidence for a predisposition gene localization on chromosome arm 9q, and suggestive evidence for at least one other locus on chromosome 1. In summary, we will create a population-based resource of surgically treated POP cases, we will pursue established and new methods to identify and localize predisposition genes affecting POP, and we will begin a detailed search for the chromosome 9 gene we have localized. PUBLIC HEALTH RELEVANCE: This research has a major potential to affect public health in the prevention of PFDs: we may be able to identify high risk populations who can be identified at a young age, studied and possibly targeted for prevention; and at a later stage in the development of PFDs, special interventions can be studied and possibly implemented in women at risk for recurrence of their condition. Someday, identification of these high risk populations may be as general as familial risk, or as specific as specific gene screening.