Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
CEINGE Biotecnologie Avanzate s.c.a r.l., Naples, Italy.
HLA. 2024 May;103(5):e15515. doi: 10.1111/tan.15515.
Although a number of susceptibility loci for neuroblastoma (NB) have been identified by genome-wide association studies, it is still unclear whether variants in the HLA region contribute to NB susceptibility. In this study, we conducted a comprehensive genetic analysis of variants in the HLA region among 724 NB patients and 2863 matched controls from different cohorts. We exploited whole-exome sequencing data to accurately type HLA alleles with an ensemble approach on the results from three different typing tools, and carried out rigorous sample quality control to ensure a fine-scale ancestry matching. The frequencies of common HLA alleles were compared between cases and controls by logistic regression under additive and non-additive models. Population stratification was taken into account adjusting for ancestry-informative principal components. We detected significant HLA associations with NB. In particular, HLA-DQB105:02 (OR = 1.61; p = 5.4 × 10) and HLA-DRB116:01 (OR = 1.60; p = 2.3 × 10) alleles were associated to higher risk of developing NB. Conditional analysis highlighted the HLA-DQB105:02 allele and its residue Ser57 as key to this association. DQB105:02 allele was not associated to clinical features worse outcomes in the NB cohort. Nevertheless, a risk score derived from the allelic combinations of five HLA variants showed a substantial predictive value for patient survival (HR = 1.53; p = 0.032) that was independent from established NB prognostic factors. Our study leveraged powerful computational methods to explore WES data and HLA variants and to reveal complex genetic associations. Further studies are needed to validate the mechanisms of these interactions that contribute to the multifaceted pattern of factors underlying the disease initiation and progression.
尽管全基因组关联研究已经确定了许多神经母细胞瘤 (NB) 的易感基因座，但 HLA 区域的变异是否会导致 NB 易感性仍不清楚。在这项研究中，我们对来自不同队列的 724 名 NB 患者和 2863 名匹配对照者的 HLA 区域中的变体进行了全面的遗传分析。我们利用外显子组测序数据，通过三种不同分型工具的结果综合方法准确地对 HLA 等位基因进行分型，并进行严格的样本质量控制，以确保精细的祖先匹配。通过加性和非加性模型的逻辑回归比较病例和对照组常见 HLA 等位基因的频率。通过调整基于祖先信息的主成分来考虑群体分层。我们检测到与 NB 相关的显著 HLA 关联。特别是，HLA-DQB105:02（OR=1.61；p=5.4×10）和 HLA-DRB116:01（OR=1.60；p=2.3×10）等位基因与较高的 NB 发病风险相关。条件分析突出了 HLA-DQB105:02 等位基因及其残基 Ser57 是这种关联的关键。在 NB 队列中，DQB105:02 等位基因与临床特征较差的结局无关。然而，源自五个 HLA 变体的等位基因组合的风险评分显示出对患者生存的显著预测价值（HR=1.53；p=0.032），这与既定的 NB 预后因素独立。我们的研究利用强大的计算方法来探索 WES 数据和 HLA 变体，并揭示复杂的遗传关联。需要进一步的研究来验证这些相互作用的机制，这些机制有助于解释导致疾病起始和进展的多方面因素。
