Intronic SNP - rs9288953 Of Suppressor Molecule Btla Confers Susceptibility To B-Cell Chronic Lymphocytic Leukemia

Abstract

The contribution of the immune system to the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) have been receiving growing attention. The increase of cancer risk in immunodeficient individuals has been documented in population and experimental studies (Gurlich et al 2007; Swann et al 2007, Smyth et al 2006). A new member of co-inhibitory molecules B - and T-lymphocyte attenuator (BTLA) that inhibits lymphocyte activation could influence cancer susceptibility (Watanabe et al 2003). A high expression of BTLA was observed on malignant B cells from chronic lymphocytic leukemia/small lymphocytic leukemia (M'Hidi et al. 2009). As BTLA synthesis depends on the rate of gene transcription and/or translation, polymorphism in the corresponding gene might result in abnormal expression and function.The aim of this studywas to evaluate possible associations between selected on the basis of literature (Fu et al 2009) single nucleotide polymorphisms (SNPs) existing within exons and introns of BTLA gene: rs9288952A>G, rs1844089G>A, rs2705535C>T and 9288953C>T and susceptibility to B-CLL.Genotyping was done using allelic discrimination method with the TaqMan SNP Genotyping Assays in 300 B-CLL patients (pts.) (203 pts. from Department of Hematology, Medical University Lodz, Poland and 97 from Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Poland (138 female/162 male) and in 417 healthy individuals (168 female/243 male) originating from the same region of Poland.The significant differences in distribution of alleles and genotypes was observed for intronic SNP -rs9288953. The frequency of T allele and T alleles carriers (CT+TT genotypes) were higher in patients than in healthy controls as compare to C allele and CC genotypes (0.458 vs. 0.375, p=0.0016; OR:1.41, 95%CI - 1.13-1.75 and 0.677 vs. 0.606, p=0.0022; OR:1.67, 95%CI- 1.16-1.2.40, respectively). None of other investigated SNPs have shown different frequency of alleles or genotypes in group of patients and controls.The haplotype analysis of rs9288952A>G, rs1844089G>A, rs2705535C>T and 9288953C>T showed that the most common haplotypes rs9288952A>G[A]/rs1844089G>A[G]/rs2705535C>T[C]/ 9288953C>T[C] (named as AGCC) and rs9288952A>G[A]/rs1844089G>A[G]/rs2705535C>T[C]/ 9288953C>T[T] (named as AGCT) which were differentiate only by variants of 9288953C>T SNP were completely contrary associated with disease susceptibility. Haplotype AGCC is associated with decreased risk of B-CLL (OR: 0.72, 95%CI-0.59-0.90 p with Bonferroni correction=0.01), while AGCT with increased risk of disease (OR: 1.42, 95%CI-1.14-1.76 p with Bonferroni correction=0.005)Our data indicated for the first time the possible role of intronic polymorphism 9288953C>T in gene encoding suppressor molecule BTLA in susceptibility to B-CLL. ReferencesFu Z, Li D, Jiang W, Wang L, Zhang J, Xu F, Pang D, Li D. Association of BTLA gene polymorphisms with the risk of malignant breast cancer in Chinese women of Heilongjiang Province. Breast Cancer Res Treat. 2010 Feb;120(1):195-202.Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007 Jul 7;370(9581):59-67.M'Hidi H, Thibult ML, Chetaille B, Rey F, Bouadallah R, Nicollas R, Olive D, Xerri L. High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia.Am J Clin Pathol. 2009 Oct;132(4):589-96.Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1-50.Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007 May;117(5):1137-46.Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, Murphy KM. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.Nat Immunol. 2003 Jul;4(7):670-9. Disclosures:No relevant conflicts of interest to declare.