Genetic Epidemiology of Pelvic Organ Prolapse

描述（由申请人提供）：盆腔器官脱垂是女性的主要健康问题，在绝经后女性中的患病率为40%。目前，脱垂的潜在病理生理学尚未得到很好的理解，治疗主要集中在终末期疾病。终末期疾病的特征是子宫或阴道完全伸出体外，由于盆腔不适和肠道和膀胱功能障碍，导致生活质量显著降低。关于脱垂的病理生理学的假设包括胶原蛋白和弹性蛋白的异常，以及平滑肌和骨骼肌的改变。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进展。一项家族性脱垂的研究确定了编码层粘连蛋白（ECM组分）的LAMC 1基因中的单核苷酸多态性（SNP）。然而，这种层粘连蛋白突变还没有在更大的，一般人群的妇女脱垂进行研究。鉴于这种疾病的复杂性，我们假设存在多个易感基因导致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LAMC 1单核苷酸多态性（rs 10911193）在一般非家族性晚期脱垂女性（III-IV期）和正常支持（0-I期）对照人群中的相关性，2）评估晚期脱垂女性和对照人群中功能性细胞外基质和肌球蛋白基因中候选遗传变异的相关性。查明患病风险高的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和个性化治疗策略。这项新的研究将促进临床科学家和遗传学家之间的宝贵合作，并推动转化医学在不断发展的泌尿妇科学领域的实施。 公共卫生相关性：盆腔器官脱垂是一种普遍的疾病，其中盆腔器官突出到身体外部，是女性的主要健康问题，并对生活质量产生负面影响。我们目前对脱垂原因的了解非常有限。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性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.