Decreased human leukocyte antigen A*02:01 frequency is associated with risk of glioma and existence of human cytomegalovirus: a case-control study in Northern China

Abstract

Background: Human leukocyte antigens (HLAs) play an important role in host defense against viral infection and tumorigenesis. Human cytomegalovirus (HCMV) has been linked to glioma development. This study investigated the relationship between HLA distribution, presence of HCMV, and glioma development in a Han Chinese population.

Methods: The study population included 150 glioma patients and 150 tumor-free brain injury control subjects (control-A) matched according to geography, ethnicity, age, and gender. HLA allele frequency was compared between the two groups using peripheral blood samples by PCR sequence-based typing. These data were also compared with HLA frequencies obtained from a Northern Chinese Han population database (control-B). HCMV DNA was detected in the peripheral blood of glioma patients and control group-A by nested PCR. The expression of HCMV proteins IE1-72 and pp65 in tumor tissues was evaluated by immunohistochemistry.

Results: The frequency of HLA-A*02:01 was decreased in glioma patients as compared to control group-A and -B (P < 0.001 and P = 0.001, respectively). The age/sex-adjusted odds ratio for HLA-A*02:01 positivity vs. negativity was 0.392 (95% confidence interval 0.225-0.683). HCMV was more frequently detected in the peripheral blood and tumor tissue of HLA-A*02:01-negative glioma patients. HLA-A*02:01 and HCMV were not associated with overall survival.

Conclusion: There is a correlation between decreased HLA-A*0201 allele frequency and glioma susceptibility.

Keywords: Glioma; HCMV; HLA; Immunology; Immunotherapy.

Fig. 1

Distribution of HLA class I alleles. The frequencies of HLA-A (a), HLA-B (b), and HLA-C (c) are shown. Control-A: 150 brain tumor-free patients diagnosed with traumatic brain injury matched with glioma patients according to age, gender, ethnicity, and geography; control-B: HLA frequencies for healthy Northern Chinese subjects obtained from a web database (http://www.allelefrequencies.net). **P < 0.01

Fig. 2

Distribution of HLA class II alleles. The frequencies of HLA-DPB1 (a), HLA-DRB1 (b) and HLA-DQB1 (c) are shown. d Stratified analyses of case–control ORs for the HLA-A*02:01 allele expressed as categorical data. ORs were adjusted for age and sex, and are shown with 95% CIs

Fig. 3

Association between HLA-A*02:01 and HCMV. a Detection of HCMV UL55 gene in the peripheral blood of glioma patients and control subjects by nested PCR. Grade II, Grade III, and Grade IV are different grades of glioma. b HCMV DNA was more frequently detected in the peripheral blood of HLA-A*02:01-negative than -positive glioma patients (36.5 vs. 8.3%, P = 0.007). c Representative micrographs from glioma cases showing IE1-72 and pp65 positivity (G1, G2, and G3) and negativity (G4). d, e Expression of HCMV proteins IE1-72 (d, 88.1 vs. 25%, P < 0.001) and pp65 (e, 73.8 vs. 25%, P < 0.001) was more frequently detected in tumor tissue of HLA-A*02:01-negative than -positive glioma patients. f Anti-HCMV IgM was more frequently detected in the serum of HLA-A*0201-negative than -positive glioma patients (21.4 vs. 4.2%, P = 0.047). g–i Prognostic value of HLA-A*02:01 allele and presence of HCMV DNA in 95 GBM patients, as determined by Kaplan–Meier analyses. Neither HLA-A*02:01 (g) nor HCMV (h) was associated with OS. The status of HCMV in conjunction with HLA-A*02:01 was also not correlated with GBM patient survival (i)