Department of Otolaryngology Head and Neck Surgery, Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai, China.
Am J Respir Crit Care Med. 2022 Dec 15;206(12):1534-1545. doi: 10.1164/rccm.202109-2044OC.
Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. Two characteristic study-wide significant loci ( < 2.63 × 10) for OSA were identified: the intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89; = 6.98 × 10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter on 20p13 (OR = 0.83; 95% CI, 0.79-0.88; = 7.57 × 10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that might be a therapeutic target, whereas riboflavin might be a therapeutic agent.
先前关于阻塞性睡眠呼吸暂停（OSA）的遗传研究在精确的病例定义、综合定量特征以及遗传功能解释方面存在局限性；因此，OSA 的遗传性仍未得到很好的解释。为了确定与 OSA 和客观睡眠相关特征相关的新的遗传变异，并探讨其功能作用。在 20590 名汉族个体（5438 例 OSA 和 15152 例对照样本）中进行了全基因组关联研究。使用人类样本和点突变 knockin 小鼠对基因功能进行了后续研究。确定了两个与 OSA 相关的具有特征性的全基因组显著位点（ < 2.63×10）：位于 6q26 的内含子变异 rs6455893（比值比 [OR] = 1.62；95%置信区间 [CI]，1.39-1.89； = 6.98×10）和位于 20p13 的核黄素转运蛋白上的错义变异 rs3746804（p.Pro267Leu）（OR = 0.83；95% CI，0.79-0.88； = 7.57×10）。此外，还确定了 18 个与定量 OSA 和客观睡眠相关特征相关的全基因组显著位点，其中 5 个超过了全基因组显著阈值。rs3746804 与血清核黄素浓度升高相关，小鼠中的相应突变增加了核黄素浓度，这表明该变异可能有助于核黄素摄取和核黄素依赖的生理活性。我们确定了几个与 OSA 和客观睡眠相关特征相关的新的全基因组显著位点。我们的发现为 OSA 的遗传结构提供了深入了解，并表明 可能是一个治疗靶点，而核黄素可能是一种治疗剂。
