BACKGROUND Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT. METHODS We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p < 0.05 using NIH DAVID functional annotation module with KEGG pathways and GO terms (n = 380) among 1112 breast cancer patients. RESULTS About 29% of patients reported acute post-RT pain. None of SNPs nor genes reached genome-wide significant level. Four SNPs showed suggestive associations with post-RT pain; rs16970540 in RFFL or near the LIG3 gene (p = 1.7 × 10-6), rs4584690, and rs7335912 in ABCC4/MPR4 gene (p = 5.5 × 10-6 and p = 7.8 × 10-6, respectively), and rs73633565 in EGFL6 gene (p = 8.1 × 10-6). Gene-based analysis suggested the potential involvement of neurotransmitters, olfactory receptors, and cytochrome P450 in post-RT pain, whereas functional analysis showed glucuronidation (FDR-adjusted p value = 9.46 × 10-7) and olfactory receptor activities (FDR-adjusted p value = 0.032) as the most significantly enriched biological features. CONCLUSIONS This is the first GWAS suggesting that post-RT pain is a complex polygenic trait influenced by many biological processes and functions such as glucuronidation and olfactory receptor activities. If validated in larger populations, the results can provide biological targets for pain management to improve cancer patients' quality of life. Additionally, these genes can be further tested as predictive biomarkers for personalized pain management.

中文翻译：

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乳腺癌患者急性放疗后疼痛的全基因组富集通路分析：一项前瞻性队列研究。


背景辅助放射治疗（RT）会增加发生疼痛的风险；然而，放疗相关疼痛的分子机制仍不清楚。当前的研究旨在确定临床相关的急性放疗后疼痛的易感位点和丰富的途径，定义为放疗完成时出现中度至重度疼痛（疼痛评分≥4）。方法 我们对 1,344,832 个单核苷酸多态性 (SNP) 进行了全基因组关联研究 (GWAS)，使用 PLINK 基于集合的测试对 19,621 个基因进行了基于基因的分析，并对 875 个基因的基因列表进行了功能富集分析在 1112 名乳腺癌患者中使用 NIH DAVID 功能注释模块以及 KEGG 通路和 GO 术语 (n = 380)，p < 0.05。结果 约 29% 的患者报告出现放疗后急性疼痛。 SNP 和基因均未达到全基因组显着水平。四个 SNP 显示出与放疗后疼痛的提示性关联； RFFL 中或 LIG3 基因附近的 rs16970540 (p = 1.7 × 10-6)、ABCC4/MPR4 基因中的 rs4584690 和 rs7335912 (分别为 p = 5.5 × 10-6 和 p = 7.8 × 10-6) 以及 rs73633565 EGFL6 基因（p = 8.1 × 10-6）。基于基因的分析表明神经递质、嗅觉受体和细胞色素 P450 可能参与 RT 后疼痛，而功能分析显示葡萄糖醛酸化（FDR 调整后的 p 值 = 9.46 × 10-7）和嗅觉受体活性（FDR 调整后的 p 值 = 9.46 × 10-7）和嗅觉受体活性（FDR 调整后的 p 值） value = 0.032）作为最显着富集的生物学特征。结论 这是第一个 GWAS 表明放疗后疼痛是一种复杂的多基因特征，受到许多生物过程和功能（如葡萄糖醛酸化和嗅觉受体活性）的影响。 如果在更大的人群中得到验证，结果可以为疼痛管理提供生物学目标，以改善癌症患者的生活质量。此外，这些基因可以作为个性化疼痛管理的预测生物标志物进行进一步测试。