Guzman Valeska B, Yambartsev Anatoly, Goncalves-Primo Amador, Silva Ismael D C G, Carvalho Carmen R N, Ribalta Julisa C L, Goulart Luiz Ricardo, Shulzhenko Natalia, Gerbase-Delima Maria, Morgun Andrey
Immunogenetics Division, Pediatrics Department, Federal University of São Paulo, SP, Brazil.
Hum Mol Genet. 2008 Jun 15;17(12):1838-44. doi: 10.1093/hmg/ddn077. Epub 2008 Mar 12.
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.
宫颈癌是一种具有多种环境和遗传决定因素的复杂疾病。在本研究中，我们使用单基因座和多基因座分析方法，探寻免疫反应基因多态性与宫颈癌之间的关联。在来自三个独立病例/对照样本集的患者和健康个体中，共测定了分布于CD28、CTLA4、ICOS、PDCD1、FAS、TNFA、IL6、IFNG、TGFB1和IL10基因中的14个单核苷酸多态性（SNP）。前两个样本集由白人个体组成（一组有82例病例和85例对照，另一组有83例病例和85例对照），第三个样本集由非白人个体组成（64例病例和75例对照）。多基因座分析显示，三种三基因型组合[CD28 +17(TT)/IFNG +874(AA)/TNFA -308(GG)、CD28 +17(TT)/IFN +847(AA)/PDCD1 +7785(CT)以及CD28 +17(TT)/IFNG +874(AA)/ICOS +1564(TT)]在癌症患者中的频率更高（P < 0.01，蒙特卡洛模拟）。我们推测这种双基因型[CD28(TT)和IFNG(AA)]组合可能对观察到的关联起主要作用。为解决这个问题，我们分析了三组合并后CD28(TT)、IFNG(AA)基因型组合的频率，并观察到其在患者中增加（Fisher精确检验，P = 0.0011）。第三个多态性的贡献未达到统计学意义（P = 0.1）。进一步分析表明，CD28和IFNG之间的基因-基因相互作用可能导致宫颈癌易感性。我们的结果显示CD28和IFNG基因在宫颈癌易感性方面存在上位效应，这一发现可能有助于更好地理解疾病发病机制。此外，本文提出的新分析方法可能有助于提高未来全基因组多基因座研究的统计效力。
