Susceptibility Genes for Erectile Dysfunction

 描述(由申请人提供)：勃起功能障碍(ED)在美国每5名男性中就有1名受到影响，每年的医疗支出超过40亿美元。ED的治疗模式涉及一种反复尝试的方法，重复就诊的成本现在超过了手术成本。没有候选分子显示出作为高危或疾病分层标志物的临床潜力，以促进靶向治疗或预防ED。基因方法可以通过机械、药物和生物标记物的发现来加速这种努力。越南时期双胞胎(VET)登记处的遗传率为0.32，表明ED风险的不明变异指向遗传影响。在选定的人群中进行的小型研究表明，特定的变异对ED风险和对磷酸二酯酶5型抑制剂(PDE5i)柠檬酸西地那非的反应有影响。如果没有复制，这些发现就无法推动医疗保健领域的翻译性进步。我们假设基因变异与ED的发病机制和进展/严重程度有关。Kaiser Permanente(KP)基因、环境和健康研究计划(RPGEH)、电子病历和基因组学(Emerge)网络和动脉粥样硬化多种族研究(MESA)之间的合作将把创新的表型与现有的和归因于基因的基因相结合，成为拟议的全基因组关联研究(GWAS)的一种经济高效的策略。我们还将重点阐明糖尿病男性这一高危人群对勃起功能障碍的基因贡献。识别与ED相关的基因和分子网络以及临床严重程度的测量将极大地促进我们对ED的发病机制的理解。

 DESCRIPTION (provided by applicant): Erectile dysfunction (ED) affects 1 in 5 men in the United States and has annual healthcare expenditures exceeding $4 billion. The treatment paradigm for ED involves a trial-and-error approach, with the costs of repeated clinic visits now exceeding surgical costs. No candidate molecule has shown clinical potential as a marker of high risk or disease stratification to facilitate either targeted therapy or the prevention of ED. Genetic approaches can accelerate such efforts through mechanistic, drug, and biomarker discovery. Unexplained variation in ED risk points toward genetic influences, supported by heritability of 0.32 in the Vietnam Era Twin (VET) Registry. Small studies in selected populations suggest the influence of specific variants on ED risk and on response to the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil citrate. Without replication, these findings cannot drive translational advances in care. We hypothesize that genetic variants are associated with ED pathogenesis and progression/severity. Collaboration within the Kaiser Permanente (KP) Research Program in Genes, Environment and Health (RPGEH), electronic Medical Record and Genomics (eMERGE) Network, and the Multiethnic Study of Atherosclerosis (MESA) will combine innovative phenotyping with existing and imputed genotypes in a cost-effective strategy of proposed genome-wide association studies (GWAS). We will also focus on elucidating the genetic contribution to ED among diabetic men, a high-risk population. Identifying genes and molecular networks associated with ED and clinical measures of severity will substantially advance our understanding of the disease mechanisms of ED.