Li Zhizhou, Wang Maoyu, Zeng Shuxiong, Wang Ziwei, Ying Yidie, Chen Qing, Zhang Chen, He Wei, Sheng Chaoyang, Wang Yi, Zhang Zhensheng, Xu Chuanliang, Wang Huiqing
Department of Urology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China.
World J Mens Health. 2025 Jul;43(3):616-632. doi: 10.5534/wjmh.240062. Epub 2024 Sep 24.
Evidence of an association between leukocyte telomere length (LTL) and prostate cancer (PCa) is accumulating; however, their shared genetic basis remains unclear.
Using summary statistics obtained from the genome-wide association study (GWAS), we quantified the global and local genetic correlations between two traits. Subsequently, we identified potential pleiotropic loci, common tissue-enriched regions, and risk gene loci while inferring assumed causal relationships.
Our study demonstrated a global genetic correlation between LTL and PCa (genetic correlation=0.066, p=0.017), which was further confirmed in local genomic regions. Cross-trait GWAS meta-analysis revealed 44 shared loci, including 10 novel pleiotropic single nucleotide polymorphisms appearing concurrently in significant local genetic correlation regions. Notably, two new loci (rs9419958; rs3730668) were additionally validated to co-localize. For the first time, we identified a significant shared genetic enrichment of both traits in the small intestine tissue at the terminal ileum, with functional genes in this region affecting both LTL and PCa. Concurrently, Mendelian randomization analysis indicated a positive causal relationship between LTL and PCa.
In conclusion, our study makes a significant contribution to the ongoing debate concerning the potential association between longer LTL and a higher risk of PCa. Additionally, we provide new evidence for the development of therapeutic targets for PCa and propose new directions for future risk prediction in this regard.
白细胞端粒长度（LTL）与前列腺癌（PCa）之间存在关联的证据正在不断积累；然而，它们共同的遗传基础仍不清楚。
利用从全基因组关联研究（GWAS）获得的汇总统计数据，我们量化了两个性状之间的全局和局部遗传相关性。随后，我们在推断假定的因果关系的同时，确定了潜在的多效性基因座、常见的组织富集区域和风险基因座。
我们的研究表明LTL与PCa之间存在全局遗传相关性（遗传相关性=0.066，p=0.017），这在局部基因组区域得到了进一步证实。跨性状GWAS荟萃分析揭示了44个共享基因座，包括10个新的多效性单核苷酸多态性，它们同时出现在显著的局部遗传相关性区域。值得注意的是，另外两个新基因座（rs9419958；rs3730668）被验证为共定位。我们首次在回肠末端的小肠组织中发现了这两个性状显著的共享遗传富集，该区域的功能基因同时影响LTL和PCa。同时，孟德尔随机化分析表明LTL与PCa之间存在正向因果关系。
总之，我们的研究为正在进行的关于较长LTL与较高PCa风险之间潜在关联的辩论做出了重大贡献。此外，我们为PCa治疗靶点的开发提供了新证据，并为此方面未来的风险预测提出了新方向。
