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MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2008 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 9, no 7, 613-623 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 9, no 7, 613-623 p.
Keyword [en]
cervical cancer, DQB1, TNF, LTA, TAP1, TAP2
National Category
Medical and Health Sciences
Research subject
URN: urn:nbn:se:uu:diva-98057DOI: 10.1038/gene.2008.58ISI: 000260228500005PubMedID: 18650831OAI: oai:DiVA.org:uu-98057DiVA: diva2:173225
Available from: 2009-02-20 Created: 2009-02-04 Last updated: 2013-02-26Bibliographically approved
In thesis
1. Contribution of Immunogenetic Factors in Susceptibility to Cervical Cancer
Open this publication in new window or tab >>Contribution of Immunogenetic Factors in Susceptibility to Cervical Cancer
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cervical cancer is the second most common cancer in women worldwide. Persistent infection by an oncogenic type of human papillomavirus (HPV) is a necessary but not sufficient cause and there is also a genetic component. This thesis aims to identify host genetic risk factors for cervical cancer based on the hypothesis that susceptibility is affected by genetic variation in the immune response towards HPV infection.

Paper I analyzed allergy in sons and cervical cancer in their mothers, and revealed an inverse association between cervical cancer and allergy across generations. Mothers of allergic sons have a lower incidence of cervical cancer, supporting the importance of immunogenetic factors. Paper II investigated the HPV type in 1079 women diagnosed 1965-1993. All women were from families with at least two affected. It appeared that HPV 16 was becoming less common with time. There was no evidence that related women were prone to infection by the same type, indicating that the immunogenetic factors act in a general, rather than an HPV type specific, manner. Paper III and IV analysed the association of candidate genes with susceptibility to cervical cancer in 1306 women with cervical cancer in situ and 288 unrelated controls. Paper III showed the association of variation in the two immune response genes chemokine receptor 2 (CCR-2) and interleukin 4 receptor (IL-4R) with cervical cancer. In paper IV variation at several loci in the MHC region was studied and the importance of the HLA class II locus DQB1 emphasized.

This thesis work supports the contribution of genes of the immune system to cervical cancer susceptibility. The genetic risk factors so far identified account for only a part of the genetic susceptibility, which implies that other yet undiscovered variants of importance remain to be identified.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 55 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 419
National Category
Medical Genetics
urn:nbn:se:uu:diva-9552 (URN)978-91-554-7410-2 (ISBN)
Public defence
2009-03-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2009-02-20 Created: 2009-02-04 Last updated: 2009-02-20Bibliographically approved

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Ivansson, EmmaMagnusson, JessicaGyllensten, Ulf
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