Ji Enting, Wang Ze, Zhong Ran, Lu Yao, Zheng Ruqun, Ning Shuting, Hu Min, Li Juan, Lai Maohua, Xue Guowei, Ma Hongxia
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
Department of Tranditional Chinese Medicine, Institute of International Traditional and Western Medicine of Guangzhou Medical University, Guangzhou 510260, China.
J Clin Endocrinol Metab. 2025 Aug 7;110(9):2698-2707. doi: 10.1210/clinem/dgaf276.
Observational studies have shown an association between polycystic ovary syndrome (PCOS) and asthma-related traits. However, whether this association is genetically driven or arises from observational biases remains unclear.
This study integrated data from 10 074 PCOS cases and asthma-related traits obtained from the UK Biobank and FinnGen cohorts. Global and local genetic architectures were examined using pleiotropic analysis under the composite null hypothesis, functional mapping and annotation of genetic associations, and fine-mapping credible set analysis. Drug database mining was employed to identify pleiotropic genes as potential therapeutic targets. Tissue and cell enrichment analyses were conducted to uncover shared biological mechanisms.
We identified 3 novel significant genetic loci for asthma subtypes (2 for allergic asthma and 1 for childhood asthma). A positive overall genetic correlation between PCOS and asthma-related traits was observed. We discovered 5 pleiotropic causal regions encompassing 13 genes, with ERBB3 emerging as a potential central gene contributing to the shared pathophysiology of PCOS and asthma-related traits. Additionally, drug repositioning analysis suggested anakinra and artenimol as potential therapeutic candidates for PCOS and asthma comorbidity. The linkage disequilibrium score for the specific expression of genes analysis, along with transcriptome-wide association studies, further identified gene expression patterns at the tissue/cell level in the hypothalamo-pituitary, exocrine/endocrine, respiratory, and urogenital systems.
Our findings provide novel insights into the genetic basis and biological processes underlying the association between PCOS and asthma-related traits, warranting evaluation of whether PCOS-specific asthma risk assessment could improve clinical outcomes.
观察性研究表明多囊卵巢综合征（PCOS）与哮喘相关特征之间存在关联。然而，这种关联是由基因驱动还是源于观察性偏倚仍不清楚。
本研究整合了来自英国生物银行和芬兰基因队列的10074例PCOS病例及哮喘相关特征的数据。在复合无效假设下，使用多效性分析、基因关联的功能定位和注释以及精细定位可信集分析来检查全局和局部遗传结构。采用药物数据库挖掘来识别多效性基因作为潜在的治疗靶点。进行组织和细胞富集分析以揭示共同的生物学机制。
我们确定了3个新的哮喘亚型显著遗传位点（2个用于过敏性哮喘，1个用于儿童哮喘）。观察到PCOS与哮喘相关特征之间存在总体正遗传相关性。我们发现了5个包含13个基因的多效性因果区域，其中ERBB3成为一个潜在的核心基因，促成了PCOS与哮喘相关特征的共同病理生理学。此外，药物重新定位分析表明阿那白滞素和阿替莫尔是PCOS和哮喘合并症的潜在治疗候选药物。基因特异性表达分析的连锁不平衡评分以及全转录组关联研究，进一步确定了下丘脑 - 垂体、外分泌/内分泌、呼吸和泌尿生殖系统在组织/细胞水平的基因表达模式。
我们的研究结果为PCOS与哮喘相关特征之间关联的遗传基础和生物学过程提供了新的见解，有必要评估PCOS特异性哮喘风险评估是否可以改善临床结局。
