Variation in HLA class I antigen-processing genes and susceptibility to human papillomavirus type 16-associated cervical cancer.
BACKGROUND
Persistent infection with human papillomavirus type 16 (HPV16) is a primary etiological factor for the development of cervical cancer. Genes involved in antigen processing influence both the repertoire of antigens presented by HPV16-infected cells and the nature of HPV16-specific immune responses. Genetic variation in these genes may affect protein structure and function and, consequently, the ability of an individual to clear HPV infection.


METHODS
Thirty-five single-nucleotide polymorphisms (SNPs) in 5 genes (LMP2, TAP1, LMP7, TAP2, and Tapasin) were investigated for association with susceptibility to HPV16-associated cervical cancer. Sequencing of these genes resulted in the discovery of 15 previously unreported SNPs. Microsphere-array flow cytometry-based genotyping was conducted on 787 samples from Hispanic and non-Hispanic white women (241 randomly selected control subjects, 205 HPV16-positive control subjects, and 341 HPV16-positive case subjects with cervical cancer).


RESULTS
For 9 SNPs, 8 of which had not previously been reported in the context of cervical cancer, there were statistically significant differences between the genotype distribution in case subjects and that in control subjects. Haplotype analysis of 3 haplotype blocks revealed 3 haplotypes with significant differences in frequency in case-control comparisons. Both HPV16-specific and non-type-specific differences in genotype distribution were seen.


CONCLUSIONS
Genes involved in antigen processing for HLA class I presentation may contribute to susceptibility to cervical cancer.
Deshpande
Alina
A
Decision Applications Division, Los Alamos National Laboratory, Los Alamos, California, USA.
Wheeler
Cosette M
CM
Hunt
William C
WC
Peyton
Cheri L
CL
White
P Scott
PS
Valdez
Yolanda E
YE
Nolan
John P
JP
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics; D016022:Case-Control Studies; D003546:Cysteine Endopeptidases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D012016:Reference Values; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; C073119:TAP1 protein, human; C107762:tapasin; C071313:LMP-2 protein; C071692:TAP2 protein, human; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex