The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival,American Journal of Human Genetics

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The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2022-05-11 , DOI: 10.1016/j.ajhg.2022.04.011
Geno Guerra ₁ , Linda Kachuri ₂ , George Wendt ₁ , Helen M Hansen ₁ , Steven J Mack ₃ , Annette M Molinaro ₄ , Terri Rice ₁ , Paige Bracci ₂ , John K Wiencke ₅ , Nori Kasahara ₆ , Jeanette E Eckel-Passow ₇ , Robert B Jenkins ₈ , Margaret Wrensch ₉ , Stephen S Francis ₁₀

Affiliation

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Pediatrics, University of California, San Francisco, Oakland, CA, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA.

Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study, we leveraged genetic predictors of antibody response to 12 viral antigens to investigate the relationship with glioma risk and survival. Genetic reactivity scores (GRSs) for each antigen were derived from genome-wide-significant (p < 5 × 10⁻⁸) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution by using data from 3,418 glioma-affected individuals subtyped by somatic mutations and 8,156 controls. Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p < 0.01). GRS_ZEBRA and GRS_MCV were associated in opposite directions with risk of IDH wild-type gliomas (OR_ZEBRA = 0.91, p = 0.0099/OR_MCV = 1.11, p = 0.0054). GRS_EBNA was associated with both increased risk for IDH mutated gliomas (OR = 1.09, p = 0.040) and improved survival (HR = 0.86, p = 0.010). HLA-DQA1^∗03:01 was significantly associated with decreased risk of glioma overall (OR = 0.85, p = 3.96 × 10⁻⁴) after multiple testing adjustment. This systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral-based therapies in glioma treatment.

中文翻译：

病毒抗原反应的免疫遗传学与亚型特异性神经胶质瘤的风险和生存相关

神经胶质瘤是一种高度致命的癌症，具有具有重要预后意义的分子亚型，且已知的危险因素很少。多项研究表明感染与神经胶质瘤易感性有关，但证据仍不一致。人类白细胞抗原 (HLA) 区域的遗传变异可调节宿主对感染的反应，并与神经胶质瘤风险相关。在这项研究中，我们利用对 12 种病毒抗原的抗体反应的遗传预测因子来研究与神经胶质瘤风险和生存的关系。每种抗原的遗传反应性评分 (GRS) 源自英国生物银行队列中与免疫球蛋白 G 抗体反应相关的全基因组显着 (p < 5 × 10 ^-8 ) 变异。我们使用来自 3,418 名受体细胞突变亚型的神经胶质瘤影响的个体和 8,156 名对照者的数据，对以两视野分辨率估算的每个 GRS 和 HLA 等位基因的神经胶质瘤风险和生存进行了平行分析。 Epstein-Barr 病毒 (EBV) ZEBRA 和 EBNA 抗原以及默克尔细胞多瘤病毒 (MCV) VP1 抗原的基因反应评分与神经胶质瘤风险和生存相关（Bonferroni 校正 p < 0.01）。 GRS _ZEBRA和 GRS _MCV与IDH野生型神经胶质瘤的风险呈相反的相关性（OR _ZEBRA = 0.91，p = 0.0099/OR _MCV = 1.11，p = 0.0054）。 GRS _EBNA与IDH突变神经胶质瘤风险增加（OR = 1.09，p = 0.040）和生存改善相关（HR = 0.86，p = 0.010）。经过多次测试调整后，HLA-DQA1 ^* 03:01与神经胶质瘤总体风险降低显着相关（OR = 0.85，p = 3.96 × 10 ^-4 ）。这项对病毒抗原反应性遗传决定因素在神经胶质瘤风险和生存中的作用的系统研究提供了对神经胶质瘤发病机制的复杂免疫基因组机制的深入了解。这些结果可能为基于抗病毒的疗法在神经胶质瘤治疗中的应用提供参考。

更新日期：2022-05-11

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