Differences in genetic variation in antigen-processing machinery components and association with cervical carcinoma risk in two Indonesian populations.

Akash M Mehta,Santoso Cornian,Jessica N I Vet,Gert J Fleuren,I G D Surya,Gatot Purwoto,Alexander A Peters,Vivian M Spaans,Nyoman Bayu Mahendra,Elisabeth M Osse,Ekaterina S Jordanova

doi:10.1007/s00251-015-0834-5

Abstract

Genetic variation of antigen-processing machinery (APM) components has been shown to be associated with cervical carcinoma risk and outcome in a genetically homogeneous Dutch population. However, the role of APM component single nucleotide polymorphisms (SNPs) in genetically heterogeneous populations with different distributions of human papillomavirus (HPV) subtypes remains unclear. Eleven non-synonymous, coding SNPs in the TAP1, TAP2, LMP2, LMP7 and ERAP1 genes were genotyped in cervical carcinoma patients and healthy controls from two distinct Indonesian populations (Balinese and Javanese). Individual genotype and allele distributions were investigated using single-marker analysis, and combined SNP effects were assessed by haplotype construction and haplotype interaction analysis. Allele distribution patterns in Bali and Java differed in relation to cervical carcinoma risk, with four ERAP1 SNPs and one TAP2 SNP in the Javanese population showing significant association with cervical carcinoma risk, while in the Balinese population, only one TAP2 SNP showed this association. Multimarker analysis demonstrated that in the Javanese patients, one specific haplotype, consisting of the ERAP1-575 locus on chromosome 5 and the TAP2-379 and TAP2-651 loci on chromosome 6, was significantly associated with cervical carcinoma risk (global P = 0.008); no significant haplotype associations were found in the Balinese population. These data indicate not only that genetic variation in APM component genes is associated with cervical carcinoma risk in Indonesia but also that the patterns of association differ depending on background genetic composition and possibly on differences in HPV type distribution.

Highlights

The antigen-processing machinery (APM) comprises various components working together to determine the presentation of peptides derived from intracellular proteins by human leucocyte antigen (HLA) class I molecules (Heemels and Ploegh 1995)
We have demonstrated that various single nucleotide polymorphisms (SNPs) in the low molecular weight peptide 7 (LMP7), TAP2 and ERAP1 genes were significantly associated with risk of developing cervical carcinoma in the Dutch population (Mehta et al 2007)
To ascertain the extent to which APM genetic variation may contribute to cervical carcinoma risk in regions in which human papilloma virus (HPV) is virtually endemic, we have studied the genotypes and genotype interactions of a previously reported set of SNPs in distinct Indonesian populations from Java and Bali

Summary

Introduction

The antigen-processing machinery (APM) comprises various components working together to determine the presentation of peptides derived from intracellular proteins by human leucocyte antigen (HLA) class I molecules (Heemels and Ploegh 1995). Defects in the APM have been shown to be associated with progression and impaired survival in various tumours (Facoetti et al 2005; Meissner et al 2005; Seliger et al 2006). Immunogenetics (2015) 67:267–275 presentation 1 (TAP1) and low molecular weight peptide 7 (LMP7) is significantly associated with decreased survival in human papilloma virus (HPV) associated cervical carcinoma (Mehta et al 2008). We have demonstrated that various single nucleotide polymorphisms (SNPs) in the LMP7, TAP2 and ERAP1 genes were significantly associated with risk of developing cervical carcinoma in the Dutch population (Mehta et al 2007). Two ERAP1 SNPs were found to be significantly associated with poor survival in Dutch cervical cancer patients (Mehta et al 2009)

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