Kobayashi Takuro, Hachiya Tsuyoshi, Ikehata Yoshihiro, Horie Shigeo
Department of Urology, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Department of Advanced Informatics for Genetic Diseases, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Front Aging. 2023 May 31;4:1176451. doi: 10.3389/fragi.2023.1176451. eCollection 2023.
Genomic instability is a significant hallmark of aging and has a major impact on aging biology. Mosaic loss of chromosome Y (mLOY) in blood cells is a common chromosomal abnormality in aging men and is considered an indicator of genomic instability. Previous studies have indicated a connection between mLOY and prostate cancer risk, but the causal relationship has not been fully established. To determine the causal effect of mLOY on prostate cancer, we conducted a Mendelian Randomization (MR) study in two ancestral groups. We utilized 125 and 42 mLOY-associated variants as instrumental variables (IVs) in European and East Asian GWAS of prostate cancer, respectively. Summary-level data on prostate cancer was obtained from the PRACTICAL consortium (79,148 cases and 61,106 controls of European ancestry) and the Biobank Japan consortium (5,408 cases and 103,939 controls of East Asian ancestry). A single population was used to assess the causal relationship in East Asian ancestry. Our main method for obtaining MR results was inverse-variance weighted (IVW), and we conducted sensitivity analyses to confirm the robustness of our results. Finally, we combined the estimates from both sources using a fixed-effects meta-analysis. Our MR analysis using the IVW method showed that a one-unit increase in genetically predicted mLOY was associated with an increased risk of prostate cancer in the PRACTICAL consortium (OR = 1.09%, 95% CI: 1.05-1.13, = 1.2 × 10), but not in the Biobank Japan consortium (OR = 1.13%, 95% CI: 0.88-1.45, = 0.34). Sensitivity analyses robustly indicated increased odds ratios for prostate cancer with every one-unit increase in genetically predicted mLOY for the PRACTICAL consortium. Furthermore, mLOY was found to be associated with prostate cancer risk in a meta-analysis of both sources (OR = 1.09%, 95% CI: 1.05-1.13, = 8.0 × 10). Our MR study provides strong evidence that higher mLOY increases the risk of prostate cancer. Preventing mLOY may be a means of reducing the risk of developing prostate cancer.
基因组不稳定是衰老的一个重要标志，对衰老生物学有重大影响。血细胞中Y染色体的嵌合缺失（mLOY）是老年男性常见的染色体异常，被认为是基因组不稳定的一个指标。先前的研究表明mLOY与前列腺癌风险之间存在联系，但因果关系尚未完全确立。为了确定mLOY对前列腺癌的因果效应，我们在两个祖先群体中进行了孟德尔随机化（MR）研究。我们分别在欧洲和东亚前列腺癌全基因组关联研究（GWAS）中使用125个和42个与mLOY相关的变异作为工具变量（IV）。前列腺癌的汇总数据来自PRACTICAL联盟（79148例欧洲血统病例和61106例对照）和日本生物银行联盟（5408例东亚血统病例和103939例对照）。在东亚血统中使用单一人群来评估因果关系。我们获得MR结果的主要方法是逆方差加权（IVW），并进行敏感性分析以确认结果的稳健性。最后，我们使用固定效应荟萃分析合并了来自两个来源的估计值。我们使用IVW方法的MR分析表明，在PRACTICAL联盟中，遗传预测的mLOY每增加一个单位，前列腺癌风险增加（比值比[OR]=1.09%，95%置信区间[CI]：1.05-1.13，P=1.2×10），但在日本生物银行联盟中并非如此（OR=1.13%，95%CI：0.88-1.45，P=0.34）。敏感性分析有力地表明，在PRACTICAL联盟中，遗传预测的mLOY每增加一个单位，前列腺癌的比值比就会增加。此外，在对两个来源的荟萃分析中发现mLOY与前列腺癌风险相关（OR=1.09%，95%CI：1.05-1.13，P=8.0×10）。我们的MR研究提供了强有力的证据，表明较高水平的mLOY会增加前列腺癌风险。预防mLOY可能是降低患前列腺癌风险的一种手段。
