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Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women

Genes & Immunity volume 12, pages 605–614 (2011)Cite this article

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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.

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Acknowledgements

This study was supported by grants from the Swedish Cancer Foundation and the Knut and Alice Wallenberg Foundation to Ulf Gyllensten. Henry Erlich is employed by Roche Molecular Systems who kindly provided reagents and protocols for HLA-DPB1 typing. The population allele and genotype frequencies were based on samples regionally selected from Sweden obtained from the data source funded by the Nordic Center of Excellence in Disease Genetics. The study from which control set 1 originated was supported by Novartis Pharmaceuticals, Sigrid Juselius Foundation, Folkhälsan Research Foundation and the Swedish Research Council Linné grant. The study from which control sets 2 and 3 originated was supported by grants from the National Cancer Institute (CA106523, CA105055, CA95052, CA112517, CA58236, CA86323); Department of Defense (PC051264); Swedish Cancer Society; and Swedish Research Council.

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  1. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    E L Ivansson, I Juko-Pecirep & U B Gyllensten

  2. Roche Molecular Systems, Pleasanton, CA, USA

    H A Erlich

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  1. E L Ivansson
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Correspondence to U B Gyllensten.

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Ivansson, E., Juko-Pecirep, I., Erlich, H. et al. Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women. Genes Immun 12, 605–614 (2011). https://doi.org/10.1038/gene.2011.40

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