Genetic Epidemiology of Glioblastoma Multiforme: Confirmatory and New Findings from Analyses of Human Leukocyte Antigen Alleles and Motifs |
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Authors: | Wei Song Avima M Ruder Liangyuan Hu Yufeng Li Rong Ni Wenshuo Shao Richard A Kaslow MaryAnn Butler Jianming Tang |
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Institution: | 1. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.; 2. National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio, United States of America.; 3. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.;Cedars-Sinai Medical Center and University of California Los Angeles, United States of America |
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Abstract: | BackgroundHuman leukocyte antigen (HLA) class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM).Methodology/Principal FindingsAs an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio = 0.41, p = 0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio = 2.71, p = 0.02).Conclusions/SignificanceHLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations. |
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