title: Genetic variation of antigen processing machinery components and association with cervical carcinoma.
abstract: The antigen processing machinery (APM) plays an important role in immune recognition of virally infected and transformed cells. Defective expression of several APM components is associated with progression and clinical outcome in cervical carcinoma. Genetic variation in the genes encoding APM components is known to be associated with risk of occurrence of several malignancies. However, only limited evidence exists supporting the role of single nucleotide polymorphisms (SNPs) in APM components in cervical carcinoma. We have therefore investigated the occurrence of APM component SNP genotypes and haplotypes in cervical carcinoma. Thirteen coding SNPs in the LMP2, LMP7, TAP1, TAP2, and ERAP1 genes were genotyped in 127 cervical carcinoma patients and 124 controls. Individual genotype and allele distributions were assessed by single-marker analysis. Effects of various SNP combinations were estimated by haplotype construction and subsequent haplotype interaction analysis. Significant haplotypes were modeled on disease risk. Allele distributions at the LMP7-145, TAP2-651, ERAP1-127, and ERAP1-730 loci differed significantly between cases and controls with the major allele at the LMP7 and TAP2 loci and the minor allele at both ERAP1 loci associated with increased cervical carcinoma risk. A combination of the two haplotypes spanning these loci was associated with a three-fold increased risk (OR = 3.024; P << 0.001); approximately 12% of all cervical carcinoma occurrences were attributable to this combination. Our data indicate that combined genetic variation in the TAP2, LMP7, and ERAP1 genes is associated with increased cervical carcinoma risk.
authors: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. mehta@kg.nl
authors: Akash M
authors: AM
authors: Mehta
authors: Ekaterina S
authors: ES
authors: Jordanova
authors: Tom
authors: T
authors: van Wezel
authors: Hae-Won
authors: HW
authors: Uh
authors: Willem E
authors: WE
authors: Corver
authors: Kitty M C
authors: KM
authors: Kwappenberg
authors: Willem
authors: W
authors: Verduijn
authors: Gemma G
authors: GG
authors: Kenter
authors: Sjoerd H
authors: SH
authors: van der Burg
authors: Gert J
authors: GJ
authors: Fleuren
mesh_terms: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000626:Aminopeptidases / Q000235:genetics; D017951:Antigen Presentation; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002895:Chromosomes, Human, Pair 5; D002896:Chromosomes, Human, Pair 6; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000276:immunology
chemical_list: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; C071692:TAP2 protein, human; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex