Human Molecular Genetics Advance Access originally published online on March 12, 2008
Human Molecular Genetics 2008 17(12):1838-1844; doi:10.1093/hmg/ddn077
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Published by Oxford University Press 2008
New approach reveals CD28 and IFNG gene interaction in the susceptibility to cervical cancer
1 Immunogenetics Division, Pediatrics Department, Federal University of São Paulo, SP, Brazil 2 Mathematics and Statistics Institute, University of São Paulo, Brazil 3 Department of Gynecology, Federal University of São Paulo, SP, Brazil 4 Genetics Department, Federal University of Uberlândia, MG, Brazil 5 TCMTS "Ghost lab", LCMI, NIAID, NIH, Bethesda, MD, USA
* To whom correspondence should be addressed at: TCMTS "Ghost lab", LCMI, NIAID, NIH, 9000 Rockville Pike, Bldg 4, room 111, Bethesda, MD 20892, USA. Tel: +55 3014355817; Fax: +55 3014964286; Email: anemorgun{at}hotmail.com or morguna{at}niaid.nih.gov
Received September 19, 2007; Accepted March 5, 2008
Cervical cancer is a complex disease with multiple environmental and genetic determinants. In this study, we sought an association between polymorphisms in immune response genes and cervical cancer using both single-locus and multi-locus analysis approaches. A total of 14 single nucleotide polymorphisms (SNPs) distributed in CD28, CTLA4, ICOS, PDCD1, FAS, TNFA, IL6, IFNG, TGFB1 and IL10 genes were determined in patients and healthy individuals from three independent case/control sets. The first two sets comprised White individuals (one group with 82 cases and 85 controls, the other with 83 cases and 85 controls) and the third was constituted by non-white individuals (64 cases and 75 controls). The multi-locus analysis revealed higher frequencies in cancer patients of three three-genotype combinations [CD28+17(TT)/IFNG+874(AA)/TNFA-308(GG), CD28+17(TT)/IFN+847(AA)/PDCD1+7785(CT), and CD28 +17(TT)/IFNG+874(AA)/ICOS+1564(TT)] (P < 0.01, Monte Carlo simulation). We hypothesized that this two-genotype [CD28(TT) and IFNG(AA)] combination could have a major contribution to the observed association. To address this question, we analyzed the frequency of the CD28(TT), IFNG(AA) genotype combination in the three groups combined, and observed its increase in patients (P = 0.0011 by Fisher’s exact test). The contribution of a third polymorphism did not reach statistical significance (P = 0.1). Further analysis suggested that gene–gene interaction between CD28 and IFNG might contribute to susceptibility to cervical cancer. Our results showed an epistatic effect between CD28 and IFNG genes in susceptibility to cervical cancer, a finding that might be relevant for a better understanding of the disease pathogenesis. In addition, the novel analytical approach herein proposed might be useful for increasing the statistical power of future genome-wide multi-locus studies.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors. 
M.G.D. and A.M. are co-senior authors.