Genetic epidemiology of glioblastoma multiforme: confirmatory and new findings from analyses of human leukocyte antigen alleles and motifs.
BACKGROUND
Human 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).


RESULTS
As 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
HLA-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.
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Wei
W
Song
Avima M
AM
Ruder
Liangyuan
L
Hu
Yufeng
Y
Li
Rong
R
Ni
Wenshuo
W
Shao
Richard A
RA
Kaslow
MaryAnn
M
Butler
Jianming
J
Tang
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D001932:Brain Neoplasms / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D011379:Prognosis; D012044:Regression Analysis; D012689:Sequence Homology, Nucleic Acid; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
D006680:HLA Antigens