Deciphering gene-smoking interactions in age-related macular degeneration through cross-biobank genomic integration.

IF 1.9 4区医学 Q2 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH

Tobacco Induced Diseases Pub Date : 2025-07-29 eCollection Date: 2025-01-01 DOI:10.18332/tid/205419

Ju Guo, Yuhan Jiang, Xinran Xu, Jianhua Wang, Xueming Yao, Xiaohong Wang, Hongxi Yang, Mulin J Li, Hua Yan

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引用次数: 0

Abstract

Introduction: This study aims to identify genetic loci associated with age-related macular degeneration (AMD) and assess the interaction between genetic susceptibility and smoking history.

Methods: A meta-analysis of discovery genome-wide association studies (GWASs), involving a total of 42542 AMD patients and 920322 controls from four large-scale European cohorts, was conducted using METAL, a software tool commonly used for meta-analysis of GWAS. A polygenic risk score (PRS) was derived from the meta-analysis results for 331281 UK Biobank participants. Cox proportional hazards models evaluated interactions between genetic predisposition and smoking history at both PRS and variant levels. Logistic regression models examined plasma complement protein profiles across AMD PRS and smoking status groups.

Results: We identified two novel risk loci, OCA2 melanosomal transmembrane protein (OCA2) and nitric oxide associated 1 (NOA1). Incorporating the PRS significantly enhanced AMD risk prediction in 331281 UK Biobank participants, with the area under the curve (AUC) increasing from 0.74 to 0.76 (p=2×10^-16). During a mean follow-up of 13.6 years, Cox models revealed significant additive (relative excess risk due to interaction, RERI=0.13; 95% CI: 0.06-0.19; attributable proportion, AP=0.08; 95% CI: 0.04-0.13; synergy index, SI=1.33; 95% CI: 1.13-1.56) and multiplicative interactions (hazard ratio, HR=1.08; 95% CI: 1.03-1.14, p=2.65×10^-3) between PRS and smoking history. Variant-level interactions were prominent at complement factor H (CFH) and complement factor I (CFI) loci. Individuals who have ever smoked and high PRS exhibited dysregulated plasma proteins in the alternative, classical and lectin complement pathways.

Conclusions: This study revealed the genetic architecture of AMD and highlighted the synergistic effects of smoking and genetic risk, emphasizing the potential need to integrate genetic assessments into prevention strategies.

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通过跨生物库基因组整合解读年龄相关性黄斑变性中基因吸烟的相互作用。

本研究旨在确定与年龄相关性黄斑变性（AMD）相关的基因位点，并评估遗传易感性与吸烟史之间的相互作用。方法：使用常用的GWAS荟萃分析软件METAL，对发现全基因组关联研究（GWASs）进行荟萃分析，涉及来自四个大型欧洲队列的42542例AMD患者和920322例对照。多基因风险评分（PRS）来自331281名英国生物银行参与者的荟萃分析结果。Cox比例风险模型评估了遗传易感性和吸烟史在PRS和变异水平上的相互作用。Logistic回归模型检验了AMD PRS组和吸烟组的血浆补体蛋白谱。结果：我们发现了两个新的风险位点，OCA2黑素体跨膜蛋白（OCA2）和一氧化氮相关1 （NOA1）。纳入PRS显著增强了331281名UK Biobank参与者的AMD风险预测，曲线下面积（AUC）从0.74增加到0.76 （p=2×10-16）。在平均13.6年的随访期间，Cox模型显示了显著的可加性(相互作用导致的相对超额风险，rei =0.13；95% ci: 0.06-0.19；归属比例，AP=0.08；95% ci: 0.04-0.13；协同指数，SI=1.33；95% CI: 1.13-1.56)和多重相互作用(风险比，HR=1.08；PRS与吸烟史之间的95% CI: 1.03-1.14, p=2.65×10-3)。变异水平的相互作用在补体因子H （CFH）和补体因子I （CFI）位点上表现突出。曾经吸烟和高PRS的个体在替代、经典和凝集素补体途径中表现出血浆蛋白失调。结论：本研究揭示了AMD的遗传结构，强调了吸烟和遗传风险的协同效应，强调了将遗传评估纳入预防策略的潜在需求。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tobacco Induced Diseases SUBSTANCE ABUSE-PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH

CiteScore

5.30

自引率

5.40%

发文量

审稿时长

12 weeks

期刊介绍： Tobacco Induced Diseases encompasses all aspects of research related to the prevention and control of tobacco use at a global level. Preventing diseases attributable to tobacco is only one aspect of the journal, whose overall scope is to provide a forum for the publication of research articles that can contribute to reducing the burden of tobacco induced diseases globally. To address this epidemic we believe that there must be an avenue for the publication of research/policy activities on tobacco control initiatives that may be very important at a regional and national level. This approach provides a very important "hands on" service to the tobacco control community at a global scale - as common problems have common solutions. Hence, we see ourselves as "connectors" within this global community. The journal hence encourages the submission of articles from all medical, biological and psychosocial disciplines, ranging from medical and dental clinicians, through health professionals to basic biomedical and clinical scientists.