在我们之前的常规全基因组关联研究（GWAS）中，WWOX是与急性淋巴细胞白血病（ALL）发展相关的易感基因。如今，遗传关联分析的进步促进了对 ALL 基因组学的深入探索。我们基于 ALL GWAS 数据（包括 269 例华裔病例和 1039 例对照）在基因和通路水平上进行了两步富集分析。以下功能预测和实验用于评估候选变体和基因的遗传生物学。血清素激活的阳离子选择性通道复合体基因组是参与 ALL 发生的潜在生物学途径。其中，携带rs33940208 T等位基因的个体表现出显着降低的ALL风险[比值比(OR) = 0.71，95%置信区间(CI) = 0.53至0.96，P = 2.81 × 10-2]，而携带rs33940208 T等位基因的个体表现出显着降低的ALL风险rs6779545 的 A 等位基因显示风险增加（OR = 1.23，95% CI = 1.01 至 1.51，P = 4.11 × 10-2）。值得注意的是，这两种变异组合在一起显示出更好的预测能力，与具有 0-1 个风险等位基因的受试者相比，具有 2-4 个风险等位基因的受试者患儿童 ALL 的风险增加了 131% (Ptrend = 2.05 × 10-3) 。此外，rs33940208的T等位基因可以降低HTR3A mRNA的水平，而rs6779545的A等位基因则增加HTR3D mRNA的表达。在这项研究中，我们确定 HTR3A rs33940208 和 HTR3D rs6779545 是中国儿童 ALL 的潜在易感位点。未来的验证和功能研究将阐明潜在的分子过程，完善该疾病的预防策略。© 2024。作者获得 Springer-Verlag GmbH 德国（Springer Nature 旗下公司）的独家许可。

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.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.