Wu Hailan, Li Huan, Tang Weiwei, Di Yicheng, Zhu Yingran, Dai Wei, Zhao Ming
Department of Cadre Respiratory, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210002, People's Republic of China.
Department of Respiratory Infection and Critical Care Medicine, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.
Int J Chron Obstruct Pulmon Dis. 2025 Aug 27;20:2979-2992. doi: 10.2147/COPD.S532361. eCollection 2025.
Previous Mendelian randomization (MR) studies investigating the causal relationship between lipid traits and chronic obstructive pulmonary disease (COPD) have primarily focused on individuals of European (EUR) ancestry, limiting the generalizability of findings. This study aimed to address this limitation.
Summary-level data for individuals of East Asian (EAS), African (AFR), and Hispanic (HIS) ancestry were obtained from large-scale genetic databases. Lipid traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), were derived from the Global Lipids Genetics Consortium (GLGC). The discovery COPD dataset was sourced from the Global Biobank Meta-analysis Initiative (GBMI), while replication datasets came from the Million Veteran Program (MVP) and Biobank Japan (BBJ). Causal effects were assessed through meta-analysis across discovery and replication cohorts, supplemented by a series of sensitivity analyses, including the Steiger test, Causal Analysis Using Summary Effect Estimates (CAUSE), MRLap, RadialMR, Bonferroni correction, among others.
In the EAS population, strong evidence supported a causal relationship between genetically predicted TC levels and reduced COPD risk (OR = 0.891, 95% CI: 0.841-0.944, = 9.91×10). Additionally, the association between TG and COPD (OR = 0.827, 95% CI: 0.739-0.925, = 9.04×10) in EAS was primarily driven by the rs7350481 variant in the gene. Suggestive evidence also indicated a positive causal association between TG levels and increased COPD risk (OR = 1.438, 95% CI: 1.091-1.896, = 0.009) in the AFR population. No other significant causal relationships were detected.
This study reveals ancestry-specific causal links between lipid traits and COPD risk. The protective effect observed for TG in EAS may reflect variant-level pleiotropy rather than a true metabolic influence, warranting cautious interpretation. These findings highlight the importance of multi-ancestry analyses in contextualizing genetic associations across diverse populations.
以往研究脂质性状与慢性阻塞性肺疾病（COPD）因果关系的孟德尔随机化（MR）研究主要集中在欧洲（EUR）血统个体，限制了研究结果的普遍性。本研究旨在解决这一局限性。
从大规模遗传数据库中获取东亚（EAS）、非洲（AFR）和西班牙裔（HIS）血统个体的汇总数据。脂质性状，包括高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、甘油三酯（TG）和总胆固醇（TC），来自全球脂质遗传学联盟（GLGC）。发现COPD数据集来自全球生物银行荟萃分析倡议（GBMI），而复制数据集来自百万退伍军人计划（MVP）和日本生物银行（BBJ）。通过对发现和复制队列进行荟萃分析评估因果效应，并辅以一系列敏感性分析，包括施泰格检验、使用汇总效应估计的因果分析（CAUSE）、MRLap、RadialMR、邦费罗尼校正等。
在EAS人群中，有力证据支持基因预测的TC水平与降低COPD风险之间存在因果关系（OR = 0.891，95%CI：0.841 - 0.944， = 9.91×10）。此外，EAS人群中TG与COPD的关联（OR = 0.827，95%CI：0.739 - 0.925， = 9.04×10）主要由 基因中的rs7350481变异驱动。提示性证据还表明，AFR人群中TG水平与COPD风险增加之间存在正因果关联（OR = 1.438，95%CI：1.091 - 1.896， = 0.009）。未检测到其他显著的因果关系。
本研究揭示了脂质性状与COPD风险之间特定血统的因果联系。在EAS人群中观察到的TG保护作用可能反映了变异水平的多效性而非真正的代谢影响，需要谨慎解释。这些发现强调了多血统分析在理解不同人群遗传关联中的重要性。
