Genetic variation in the SIM1 locus is associated with erectile dysfunction.
Genetic variation in the SIM1 locus is associated with erectile dysfunction.
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DOI：
10.1073/pnas.1809872115
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发表时间：
2018-10-23
影响因子：
11.1
通讯作者：
Van Den Eeden SK
中科院分区：
文献类型：
--
作者：
Jorgenson E;Matharu N;Palmer MR;Yin J;Shan J;Hoffmann TJ;Thai KK;Zhou X;Hotaling JM;Jarvik GP;Ahituv N;Wessells H;Van Den Eeden SK
勃起功能障碍是中老年男性的常见疾病。双胞胎研究表明，大约三分之一的风险是由遗传因素造成的，与其他已知的勃起功能障碍风险因素无关。然而，由于样本量小、候选基因方法和表型分析薄弱，寻找特定基因贡献者的研究一直受到限制。因此，目前还没有确定的勃起功能障碍的遗传危险因素。这项研究发现了勃起功能障碍的特定遗传原因。勃起功能障碍影响着全球数百万男性。双胞胎研究支持勃起功能障碍背后的遗传风险因素的作用，但尚未确定特定的遗传变异。我们在北加州凯撒永久遗传流行病学成人健康和老龄化队列中的36,649名男性中进行了一项大规模的全基因组相关性研究。我们还对来自英国生物库的222358名男性进行了复制分析。在发现的队列中，我们在6号染色体上发现了一个位于单一基因家族基本螺旋-环-螺旋转录因子1(SIM1)附近的单基因座(rs17185536-T)，该基因与勃起功能障碍的风险显著相关(优势比=1.2 6，P=3.4×10−2 5)。这种关联在英国生物库的样本中重复(优势比=1.2 5，P=6.8×10−14)，并且这种影响与包括身体质量指数在内的已知勃起功能障碍风险因素无关。风险基因与SIM1位于同一拓扑结构域上，与SIM1启动子相互作用，rs17185536-T风险等位基因表现出不同的增强子活性。SIM1是瘦素-黑素皮质素系统的一部分，该系统在体重稳态和性功能方面具有既定的作用。因为与勃起功能障碍相关的变异与BMI的差异无关，我们的发现表明了一种特定于性功能的机制。
Erectile dysfunction is a common condition of men in middle and older ages. Twin studies suggest that about one-third of the risk is due to genetic factors, independent of other known erectile dysfunction risk factors. However, studies that have searched for specific genetic contributors have been limited due to small sample sizes, candidate gene approaches, and weak phenotyping. As a result, there are no confirmed genetic risk factors for erectile dysfunction. This study finds a specific genetic cause for erectile dysfunction. Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10−25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10−14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin–melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.
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