Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.
复制标题
DOI：
10.1016/j.ebiom.2021.103246
复制
发表时间：
2021-03
期刊：
影响因子：
11.1
通讯作者：
Spanish Covid HGE, GEN-COVID Multicenter Study
中科院分区：
文献类型：
--
作者：
Baldassarri M;Picchiotti N;Fava F;Fallerini C;Benetti E;Daga S;Valentino F;Doddato G;Furini S;Giliberti A;Tita R;Amitrano S;Bruttini M;Croci S;Meloni I;Pinto AM;Iuso N;Gabbi C;Sciarra F;Venneri MA;Gori M;Sanarico M;Crawley FP;Pagotto U;Fanelli F;Mezzullo M;Dominguez-Garrido E;Planas-Serra L;Schlüter A;Colobran R;Soler-Palacin P;Lapunzina P;Tenorio J;Pujol A;Castagna MG;Marcelli M;Isidori AM;Renieri A;Frullanti E;Mari F;Spanish Covid HGE, GEN-COVID Multicenter Study
虽然SARS-CoV-2感染男性和女性的情况相似，但COVID-19在男性中的结果不太有利。COVID-19严重程度的可变性可以用宿主基因组的差异来解释。我们比较了严重受影响的COVID-19患者与SARS-CoV-2 PCR阳性寡核苷酸无症状受试者的WES数据的聚氨基酸变异性。雄激素受体（AR）中较短的polyQ等位基因（≤22）在638名意大利受试者的第一个测试队列（男性和女性）中对COVID-19的严重结局提供了保护。长polyQ等位基因（≥23）和严重临床结局（p = 0.024）之间的相关性也在一个独立的年龄<60岁的西班牙男性队列中得到验证（p = 0.014）。AR long-polyQ受试者中的替吉奥较高，可能表明受体抵抗（p = 0.042 Mann-Whitney U检验）。长polyQ等位基因携带者的血清睾酮水平异常低（p = 0.0004 Mann-Whitney U检验）预测了COVID-19感染男性需要重症监护。与睾酮的已知抗炎作用一致，年龄≥60岁的长polyQ患者的CRP水平升高（p = 0.018，未解释多重检测）。我们确定了第一个基因多态性，似乎倾向于一些男人发展更严重的疾病。内分泌反馈未能通过在感染期间增加睾酮水平来克服AR信号传导缺陷，导致polyQ束成为临床结局的血清睾酮水平的主导。这些结果可能有助于设计可靠的临床和公共卫生措施，并为测试睾酮作为表达长AR polyQ重复序列的COVID-19男性的辅助治疗提供了依据。MIUR项目“Dipartimenti di Eccellenza 2018-2020”，锡耶纳大学医学生物技术系，意大利（意大利D.L. n.18 March 17，2020）和“Bando Ricerca COVID-19托斯卡纳”项目给Azienda Ospedaliero-Universitaria Senese。来自Intesa San Paolo的COVID-19研究和慈善基金的私人捐助者。
While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and “Bando Ricerca COVID-19 Toscana” project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.