Wei Shuxu, Shen Ronghuai, Lu Xiaojia, Li Xinyi, He Lingbin, Zhang Youti, Huang Xianxi, Shu Zhouwu
Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, No.57, Changping Road, Shantou, Guangdong, China.
Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, No.57, Changping Road, Shantou, Guangdong, China.
Nutr Metab (Lond). 2025 Jun 10;22(1):57. doi: 10.1186/s12986-025-00925-0.
Sleep apnea (SA) is linked to various diseases. This study examines the causal link between the gut microbiome and SA, exploring potential predictive factors and target proteins using a multi-omics approach with a Phenome-wide association study (PheWAS).
Bidirectional Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) were used to assess the genetic correlation and causal relationships between the gut microbiome and SA. Mediation analysis identified intermediate relationships involving "gut microbiome-inflammatory proteins-SA." Two-sample MR and colocalization analysis in the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) databases identified protein quantitative trait loci (pQTL) associated with SA. Validation analysis used Fenland proteins, methylation quantitative trait loci (mQTL), and expression quantitative trait loci (eQTL). PheWAS screened 29 SA-associated SNPs and matched control SNPs (4:1 ratio) from UK Biobank data chosen through MR and LDSC analyses.
Inverse-variance weighted (IVW) bidirectional MR analysis did not establish a causal link between the gut microbiome and SA. C-C motif chemokine 28 showed causal relationships in both directions (forward IVW, P = 0.0336; reverse IVW, P = 0.0336). Intermediate connections were found between the Holdemanella genus and urinary plasminogen activator levels with SA. TIMP4 protein had a significant causal relationship with SA(IVW method: P > 0.05, PH4 = 96.1%; P = 7.85 × 10, PH4 in deCODE = 97.4%). PRIM1 and BMP8 A were identified as potential influencers of SA through mQTL and eQTL analyses. PheWAS suggested body impedance and predicted mass as potential predictors of SA.
Bidirectional causal relationships exist between SA and inflammatory proteins, with TIMP4 identified as a pathogenic factor and potential therapeutic target. PRIM1 and BMP8 A may impact SA risk. Body impedance and predicted mass predict SA significantly.
睡眠呼吸暂停（SA）与多种疾病相关。本研究使用全表型关联研究（PheWAS）的多组学方法，探讨肠道微生物群与SA之间的因果关系，探索潜在的预测因素和靶蛋白。
采用双向孟德尔随机化（MR）和连锁不平衡评分回归（LDSC）来评估肠道微生物群与SA之间的遗传相关性和因果关系。中介分析确定了涉及“肠道微生物群-炎症蛋白-SA”的中间关系。在deCODE和英国生物银行药物蛋白质组学项目（UKB-PPP）数据库中进行的两样本MR和共定位分析确定了与SA相关的蛋白质定量性状位点（pQTL）。验证分析使用了芬兰蛋白质、甲基化定量性状位点（mQTL）和表达定量性状位点（eQTL）。PheWAS从通过MR和LDSC分析选择的英国生物银行数据中筛选了29个与SA相关的单核苷酸多态性（SNP）和匹配的对照SNP（4:1比例）。
逆方差加权（IVW）双向MR分析未确定肠道微生物群与SA之间的因果关系。C-C基序趋化因子28在两个方向上均显示出因果关系（正向IVW，P = 0.0336；反向IVW，P = 0.0336）。发现霍尔德曼氏菌属与尿纤溶酶原激活剂水平和SA之间存在中间联系。TIMP4蛋白与SA存在显著因果关系（IVW方法：P > 0.05，PH4 = 96.1%；P = 7.85 × 10，deCODE中的PH4 = 97.4%）。通过mQTL和eQTL分析，PRIM1和BMP8 A被确定为SA的潜在影响因素。PheWAS提示身体阻抗和预测体重是SA的潜在预测因素。
SA与炎症蛋白之间存在双向因果关系，TIMP4被确定为致病因素和潜在治疗靶点。PRIM1和BMP8 A可能影响SA风险。身体阻抗和预测体重可显著预测SA。
