多步基因集分析确定了涉及儿童急性淋巴细胞白血病易感性的HTR3家族基因
Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility
影响因子:6.90000
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
摘要
在我们以前的全基因组关联研究（GWAS）中，WWOX是与急性淋巴细胞白血病（ALL）发育相关的敏感基因。如今，遗传关联分析的进步促进了对所有基因组学的深入探索。我们根据所有GWAS数据在基因和途径水平上进行了两步富集分析，包括269例和1039例中国血统的对照。以下功能预测和实验用于评估候选变异和基因的遗传生物学。 5-羟色胺激活的阳离子选择通道复合基因基因组是参与所有发生的潜在生物学途径。其中，携带T等位基因的个人表现出明显降低所有[优势比（OR）= 0.71，95％置信区间（CI）= 0.53至0.96，P = 2.81×10-2]的风险，而具有RS6777777545的等位基因= 1.23，p = 2.81×10-2] p = 4.11×10-2）。值得注意的是，两种变体在合并后表现出更好的预测能力，与具有0-1风险等位基因的风险等位基因相比，患有2-4个风险等位基因的受试者的童年风险都增加了131％（Ptrend = 2.05×10-3）。此外，RS33940208的T等位基因可以降低HTR3A mRNA水平，而6779545卢比的等位基因增加了HTR3D mRNA的表达。在这项研究中，我们将HTR3A RS33940208和HTR3D RS6779545确定为所有中国儿童中所有人的潜在易感基因座。未来的验证和功能研究将阐明潜在的分子过程，从而完善该疾病的预防策略。
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.