Genetic Epidemiology of Pelvic Organ Prolapse

描述(申请人提供)：盆腔器官脱垂是女性的主要健康问题，绝经后女性的患病率为40%。目前，脱垂的基本病理生理机制尚不清楚，治疗主要集中在终末期疾病上。终末期疾病的特征是子宫或阴道完全突出到身体外部，由于盆腔不适以及肠道和膀胱功能障碍导致生活质量显著下降。关于脱垂的病理生理学假说包括胶原和弹性蛋白的异常，以及平滑和骨骼肌的改变。因此，细胞外基质(ECM)和肌球蛋白途径的基因突变可能导致脱垂的发生和发展。一项关于家族性脱垂的研究发现，LAMC1基因编码层粘连蛋白的单核苷酸多态性(SNP)，这是一种细胞外基质成分。然而，这种层粘连蛋白突变还没有在更大规模的脱垂女性人群中进行研究。鉴于这种疾病的复杂性质，我们假设多个易感基因的存在有助于这种假定的多基因疾病。因此，我们建议使用候选基因关联研究来研究盆腔器官脱垂的遗传流行病学。我们的具体目标是：1)评估LAMC1单核苷酸多态(Rs10911193)在晚期脱垂妇女(III-IV期)和正常支持对照组(0-I期)的一般非家族性人群中的关联性；2)评估晚期脱垂妇女和对照组中功能性细胞外基质和肌球蛋白基因候选遗传变异的关联性。确定疾病高危妇女将提供一个独特和令人兴奋的机会，以启动预防性干预措施，解决可改变的风险因素，并使治疗策略个体化。这项新颖的研究将促进临床科学家和遗传学家之间有价值的合作，并推动转化医学在不断发展的泌尿外科领域的实施。 公共卫生相关性：盆腔器官脱垂是一种常见的情况，即盆腔器官突出到身体外部，是妇女的一个主要健康问题，并对生活质量产生负面影响。我们目前对脱垂原因的了解极其有限。通过遗传学研究确定高危妇女将为实施预防性干预措施和个体化治疗建议提供独特的机会。

DESCRIPTION (provided by applicant): Pelvic organ prolapse represents a major health issue for women with a prevalence of 40% in postmenopausal women. Currently, the underlying pathophysiology of prolapse is not well understood and treatments are focused on end-stage disease. End-stage disease is characterized by complete protrusion of the uterus or vagina external to the body, resulting in a marked reduction in quality of life due to pelvic discomfort and bowel and bladder dysfunction. Hypotheses regarding the pathophysiology of prolapse include abnormalities in collagen and elastin, as well as alterations in smooth and skeletal muscles. Thus, genetic mutations in the extracellular matrix (ECM) and myosin pathways may result in the genesis and progression of prolapse. A study of familial prolapse identified a single nucleotide polymorphism (SNP) in the LAMC1 gene encoding laminin, an ECM component. However, this laminin mutation has not been studied in a larger, general population of women with prolapse. Given the complex nature of this disease, we hypothesize that the presence of multiple, susceptibility genes contribute to this presumed polygenic disease. Hence, we propose to study the genetic epidemiology of pelvic organ prolapse using a candidate gene association study. Our specific aims are: 1) to evaluate the association of the LAMC1 single nucleotide polymorphism (rs10911193) in a general, non-familial population of women with advanced prolapse (stage III-IV) and controls with normal support (stage 0-I), and 2) to assess the association of candidate genetic variants in functional extracellular matrix and myosin genes in women with advanced prolapse and controls. Identification of women at high risk for disease would provide a unique and exciting opportunity to initiate preventative interventions, address modifiable risk factors and individualize treatment strategies. This novel study will foster valuable collaboration between clinical scientists and geneticists and advance the implementation of translational medicine into the evolving field of urogynecology. PUBLIC HEALTH RELEVANCE: Pelvic organ prolapse, a prevalent condition in which the pelvic organs protrude external to the body, is a major health issue for women and negatively impacts quality of life. Our current understanding of the causes of prolapse is extremely limited. Identification of women at high risk through genetics research would provide a unique opportunity to implement preventative interventions and individualize treatment recommendations.