Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94158, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.
J Neurooncol. 2017 Nov;135(2):237-244. doi: 10.1007/s11060-017-2569-7. Epub 2017 Jul 18.
Although genome-wide association studies have identified several susceptibility loci for adult glioma, little is known regarding the potential contribution of genetic variation in the human leukocyte antigen (HLA) region to glioma risk. HLA associations have been reported for various malignancies, with many studies investigating selected candidate HLA polymorphisms. However, no systematic analysis has been conducted in glioma patients, and no investigation into potential non-additive effects has been described. We conducted comprehensive genetic analyses of HLA variants among 1746 adult glioma patients and 2312 controls of European-ancestry from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, and we imputed HLA alleles using a reference panel of 5225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the HLA region are linked, we created multigene haplotypes consisting of the genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, inclusion of a dominance term significantly improved the model for multigene haplotype HLA-DRB11501-DQA10102-DQB10602 (P = 0.002). Heterozygous carriers of the haplotype had an increased risk of glioma [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.01-1.49], while homozygous carriers were at decreased risk compared with non-carriers (OR 0.64; 95% CI 0.40-1.01). Our results suggest that the DRB11501-DQA10102-DQB10602 haplotype may contribute to the risk of glioma in a non-additive manner, with the positive dominance effect partly explained by an epistatic interaction with HLA-DRB10401-DQA10301-DQB1*0301.
尽管全基因组关联研究已经确定了几个成人脑胶质瘤的易感位点，但对于人类白细胞抗原 (HLA) 区域内遗传变异对脑胶质瘤风险的潜在贡献知之甚少。HLA 关联已在各种恶性肿瘤中得到报道，许多研究都在调查选定的候选 HLA 多态性。然而，在脑胶质瘤患者中尚未进行系统分析，也没有描述对潜在非加性效应的研究。我们对来自 GliomaScan 联盟的 1746 名成年脑胶质瘤患者和 2312 名欧洲血统对照者进行了 HLA 变体的综合遗传分析。使用 Illumina 660-Quad 阵列生成基因型数据，并使用通过下一代测序进行高分辨率 HLA 分型的 1 型糖尿病遗传学联合会的 5225 名个体的参考面板对 HLA 等位基因进行了推断。病例对照比较根据人口分层使用具有信息量的主成分进行了调整。由于 HLA 区域中不同基因座上的等位基因是连锁的，因此我们创建了由 DRB1、DQA1 和 DQB1 组成的多基因单体型。尽管在加性模型中没有一个单体型与脑胶质瘤相关，但包含显性项显著改善了 HLA-DRB11501-DQA10102-DQB10602 多基因单体型的模型 (P=0.002)。单体型的杂合携带者患脑胶质瘤的风险增加（比值比 [OR] 1.23；95%置信区间 [CI] 1.01-1.49），而纯合携带者与非携带者相比风险降低（OR 0.64；95% CI 0.40-1.01）。我们的结果表明，DRB11501-DQA10102-DQB10602 单体型可能以非加性方式导致脑胶质瘤的风险增加，阳性显性效应部分由与 HLA-DRB10401-DQA10301-DQB1*0301 的上位性相互作用解释。
