ABSTRACT
We have conducted a pathway-based analysis of genome-wide single-nucleotide polymorphism (SNP) data in order to identify genetic susceptibility factors for cervical cancer in situ. Genotypes derived from Affymetrix 500k or 5.0 arrays for 1076 cases and 1426 controls were analyzed for association, and pathways with enriched signals were identified using the SNP ratio test. The most strongly associated KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were Asthma (empirical P=0.03), Folate biosynthesis (empirical P=0.04) and Graft-versus-host disease (empirical P=0.05). Among the 11 top-ranking pathways were 6 related to the immune response with the common denominator being genes in the major histocompatibility complex (MHC) region on chromosome 6. Further investigation of the MHC revealed a clear effect of HLA-DPB1 polymorphism on disease susceptibility. At a functional level, DPB1 alleles associated with risk and protection differ in key amino-acid residues affecting peptide-binding motifs in the extracellular domains. The results illustrate the value of pathway-based analysis to mine genome-wide data, and point to the importance of the MHC region and specifically the HLA-DPB1 locus for susceptibility to cervical cancer.
Subject(s)
Carcinoma in Situ/genetics , Genetic Predisposition to Disease , HLA-DP beta-Chains/genetics , Uterine Cervical Neoplasms/genetics , Alleles , Amino Acid Motifs , Amino Acid Sequence , Exons , Female , Gene Frequency , Genome-Wide Association Study , Haplotypes , Humans , Male , Polymorphism, Single Nucleotide , Risk , Signal Transduction , Sweden , Uterine Cervical Dysplasia/geneticsABSTRACT
Cervical cancer has been associated with specific human leukocyte antigen (HLA) haplotypes/alleles and with polymorphisms at the nearby non-HLA loci TNF, LTA, TAP1 and TAP2. Distinguishing effects of individual loci in the major histocompatibility complex (MHC) region are difficult due to the complex linkage disequilibrium (LD) pattern characterized by high LD, punctuated by recombination hot spots. We have evaluated the association of polymorphism at HLA class II DQB1 and the TNF, LTA, TAP1 and TAP2 genes with cervical cancer risk, using 1306 familial cases and 288 controls. DQB1 was strongly associated; alleles *0301, *0402 and (*)0602 increased cancer susceptibility, whereas *0501 and *0603 decreased susceptibility. Among the non-HLA loci, association was only detected for the TAP2 665 polymorphism, and interallelic disequilibrium analysis indicated that this could be due to LD with DQB1. As the TAP2 665 association was seen predominantly in non-carriers of DQB1 susceptibility alleles, we hypothesized that TAP2 665 may have an effect not attributable to LD with DQB1. However, a logistic regression analysis suggested that TAP2 665 was strongly influenced by LD with DQB1. Our results emphasize the importance of large sample sizes and underscore the necessity of examining both HLA and non-HLA loci in the MHC to assign association to the correct locus.
