Wang Ze, Deng Hongsheng, Ji Enting, Lu Yao, Lu Weixiang, He Jianxing, Shao Wenlong
Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Transl Lung Cancer Res. 2025 Aug 31;14(8):3054-3066. doi: 10.21037/tlcr-2025-184. Epub 2025 Aug 22.
Lung cancer (LCA) and type 2 diabetes (T2D) are major global health burdens, with accumulating evidence suggesting a genomic link. This study systematically investigates the shared genetic architecture between LCA subtypes [small cell lung cancer (SCLC), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD)] and T2D using large-scale genome-wide association studies (GWAS).
We conducted genome-wide genetic correlation analyses using linkage disequilibrium score regression (LDSC) and local genetic correlation analyses via heritability estimation from summary statistics (HESS). Pleiotropic variants were identified using the pleiotropic analysis under composite null hypothesis (PLACO), and functional annotation was performed with functional mapping and annotation of genetic associations (FUMA). Pathway and Gene Ontology (GO) analyses were carried out using Kyoto Encyclopedia of Genes and Genomes (KEGG) and GO, and tissue-specific enrichment patterns were evaluated with LDSC for the specific expression of genes analysis (LDSC-SEG).
Our analysis revealed significant positive genetic correlations between T2D and LCA subtypes, particularly in SCLC and LUSC. Genome-wide genetic correlation analyses indicated the strongest correlation between LCA and T2D. Local genetic correlation analysis identified several genomic regions with suggestive significance. A total of 50 independent genomic risk loci were identified as pleiotropic loci, involving 34 unique chromosomal regions. Notably, the 9p21.3 region (CDKN2B-AS1) was identified in all pairwise trait analyses. Functional annotation highlighted deleterious variants in genes such as , and . Pathway analyses indicated significant enrichment in chromatin organization and metabolic regulation.
This study provides robust evidence of a shared genetic architecture between LCA subtypes and T2D, highlighting potential therapeutic targets. Future research should focus on validating these findings in larger cohorts and exploring the functional roles of the identified genes in the co-occurrence of these conditions.
肺癌（LCA）和2型糖尿病（T2D）是全球主要的健康负担，越来越多的证据表明存在基因组联系。本研究使用大规模全基因组关联研究（GWAS）系统地调查了肺癌亚型[小细胞肺癌（SCLC）、肺鳞状细胞癌（LUSC）、肺腺癌（LUAD）]与2型糖尿病之间共享的遗传结构。
我们使用连锁不平衡评分回归（LDSC）进行全基因组遗传相关性分析，并通过汇总统计数据的遗传力估计（HESS）进行局部遗传相关性分析。使用复合零假设下的多效性分析（PLACO）鉴定多效性变异，并通过遗传关联的功能映射和注释（FUMA）进行功能注释。使用京都基因与基因组百科全书（KEGG）和基因本体论（GO）进行通路和基因本体（GO）分析，并使用基因特异性表达分析的LDSC（LDSC-SEG）评估组织特异性富集模式。
我们的分析揭示了2型糖尿病与肺癌亚型之间存在显著的正遗传相关性，特别是在小细胞肺癌和肺鳞状细胞癌中。全基因组遗传相关性分析表明肺癌与2型糖尿病之间的相关性最强。局部遗传相关性分析确定了几个具有提示意义的基因组区域。总共50个独立的基因组风险位点被鉴定为多效性位点，涉及34个独特的染色体区域。值得注意的是，在所有成对性状分析中都鉴定出了9p21.3区域（CDKN2B-AS1）。功能注释突出了某些基因中的有害变异。通路分析表明在染色质组织和代谢调节方面有显著富集。
本研究提供了肺癌亚型与2型糖尿病之间共享遗传结构的有力证据，突出了潜在的治疗靶点。未来的研究应集中在更大的队列中验证这些发现，并探索所鉴定基因在这些疾病共存中的功能作用。
