多步基因集分析鉴定HTR3家族基因与儿童急性淋巴细胞白血病易感性

Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility

ARCHIVES OF TOXICOLOGY

影响因子:6.9

分区:医学2区 / 毒理学1区

发表日期:2025 Jan

作者: Xiao Liu, Honghao Guo, Meiyun Kang, Wenfeng Fu, Huiqin Li, Hongsheng Ji, Jiou Zhao, Yongjun Fang, Mulong Du, Yao Xue

DOI: 10.1007/s00204-024-03881-5

摘要

在我们之前的常规全基因组关联研究（GWAS）中，WWOX被认为是与急性淋巴细胞白血病（ALL）发生相关的易感基因。随着遗传关联分析的进展，我们对ALL的基因组学进行了更深入的探索。我们基于包括269例病例和1039例中国人对照的ALL GWAS数据，进行两步富集分析，结合基因和通路层面的分析，利用功能预测和实验验证候选变异及基因的生物学作用。分析发现，血清素激活的阳离子选择性通道复合物基因集可能在ALL发生中起作用。具体而言，携带rs33940208的T等位基因者ALL风险显著降低（比值比OR=0.71，95%置信区间CI=0.53-0.96，P=2.81×10^-2），而携带rs6779545的A等位基因者风险增加（OR=1.23，95%CI=1.01-1.51，P=4.11×10^-2）。这两个变异联合预测能力更强，携带2-4个风险等位基因的儿童患ALL的风险比携带0-1个风险等位基因者高131%（趋势P=2.05×10^-3）。此外，rs33940208的T等位基因可降低HTR3A mRNA水平，而rs6779545的A等位基因则增加HTR3D mRNA表达。本研究识别了HTR3A rs33940208和HTR3D rs6779545作为中国儿童ALL的潜在易感位点。未来的验证和功能研究将揭示其潜在的分子机制，为疾病的预防提供理论基础。

Abstract

In our previous conventional genome-wide association study (GWAS), WWOX was a susceptibility gene associated with acute lymphoblastic leukemia (ALL) development. Nowadays, advancements in genetic association analyses promote an in-depth exploration of ALL genomics. We conducted a two-step enrichment analysis at both gene and pathway levels based on ALL GWAS data including 269 cases and 1039 controls of Chinese descent. The following functional prediction and experiments were used to evaluate the genetic biology of candidate variants and genes. The serotonin-activated cation-selective channel complex gene-set was a potential biological pathway involved in ALL occurrence. Of which, individuals carrying the T allele of rs33940208 exhibited a prominent reduced risk of ALL [odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53 to 0.96, P = 2.81 × 10-2], whereas those with the A allele of rs6779545 demonstrated an increased risk (OR = 1.23, 95% CI = 1.01 to 1.51, P = 4.11 × 10-2). Notably, the two variants displayed a better prediction capability when combined, that the risk of developing childhood ALL increased by 131% in subjects with 2-4 risk alleles compared to those with 0-1 risk alleles (Ptrend = 2.05 × 10-3). In addition, the T allele of rs33940208 could reduce HTR3A mRNA level, while the A allele of rs6779545 increased HTR3D mRNA expression. In this study, we identified HTR3A rs33940208 and HTR3D rs6779545 as potential susceptibility loci for ALL in Chinese children. Future validation and functional research will elucidate the underlying molecular processes, refining preventive strategies for this disease.