Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt.
Cancer Immunol Immunother. 2021 Jul;70(7):1939-1949. doi: 10.1007/s00262-020-02797-0. Epub 2021 Jan 7.
Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs.
We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster.
A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases.
Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.
免疫检查点抑制剂（ICIs）可引起严重的免疫相关不良事件（irAEs）。宿主遗传背景可能在 irAE 易感性中起作用，因为毒性表现因患者而异，许多患者尽管继续使用 ICI，但并未出现 irAE。我们试图确定赋予 irAE 风险的潜在遗传标志物。
我们对 89 名接受 ICI 治疗的黑色素瘤患者进行了一项探索性的初步研究（44 名出现 irAE，45 名在开始治疗至少 1 年后未出现 irAE）。使用 Infinium Multi-Ethnic Global-8 v1.0 Bead Chip 进行基因分型。使用 PLINK（v1.90b3.34）提取基因型数据，并进行质量控制处理。使用 IBS 矩阵、成对群体一致性检验（p<1×10）和所有研究参与者的表型分布进行基于群体结构的聚类，得到七个基于群体结构的聚类。在分析阶段，纳入常染色体染色体上的 599931 个变体进行关联研究。使用加性遗传模型进行关联测试，使用精确的逻辑回归进行调整，以适应年龄、性别和群体聚类。
总共确定了 30 个变体或单核苷酸多态性（p<1×10），其中 12 个与 irAE 风险增加相关，其余 18 个与 irAE 风险降低相关。总体而言，鉴定出的 9 个单核苷酸多态性映射到 8 个独特的基因，这些基因与自身免疫或炎症性疾病有关。
确定了几个与 irAE 相关的遗传变异。需要进行更多更大的研究来验证这些发现，并确定它们的潜在功能相关性。
