Susceptibility Genes for Erectile Dysfunction

 描述（由申请人提供）：勃起功能障碍（艾德）影响美国五分之一的男性，每年的医疗保健支出超过40亿美元。艾德的治疗模式涉及一种试错法，现在重复诊所就诊的费用超过了手术费用。没有候选分子显示出作为高风险或疾病分层的标志物的临床潜力，以促进靶向治疗或预防ED。遗传方法可以通过机制，药物和生物标志物的发现来加速这种努力。无法解释的艾德风险变异指向遗传影响，越南时代双胞胎（VET）登记处的遗传度为0.32。在选定人群中开展的小型研究表明，特定变异对艾德风险和对磷酸二酯酶5型抑制剂（PDE 5i）枸橼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护理方面的转化进展。我们假设遗传变异与艾德的发病机制和进展/严重程度相关。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）网络以及多种族动脉粥样硬化研究（梅萨）内的合作将联合收割机创新表型与现有和估算的基因型结合在一起，采用具有成本效益的策略进行拟议的全基因组关联研究（GWAS）。我们还将重点阐明糖尿病男性（高危人群）中艾德的遗传因素。识别与艾德相关的基因和分子网络以及严重程度的临床测量将大大促进我们对ED疾病机制的理解。

 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.